High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates – Science Advances

Abstract

The emergence of several cell therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective treatment; however, scalable production of these cell therapies has become a bottleneck. To overcome this barrier, three-dimensional (3D) cell culture strategies have been considered for enhanced cell production. Here, we demonstrate a high-throughput 3D culture platform used to systematically screen 1200 culture conditions with varying doses, durations, dynamics, and combinations of signaling cues to derive oligodendrocyte progenitor cells and midbrain dopaminergic neurons from human pluripotent stem cells (hPSCs). Statistical models of the robust dataset reveal previously unidentified patterns about cell competence to Wnt, retinoic acid, and sonic hedgehog signals, and their interactions, which may offer insights into the combinatorial roles these signals play in human central nervous system development. These insights can be harnessed to optimize production of hPSC-derived cell replacement therapies for a range of neurological indications.

Stem cellsincluding adult and pluripotent subtypesoffer tremendous clinical promise for the treatment of a variety of degenerative diseases, as these cells have the capacity to self-renew indefinitely, mature into functional cell types, and thereby serve as a source of cell replacement therapies (CRTs). Human pluripotent stem cells (hPSCs) are of increasing interest for the development of CRTs due to their capacity to differentiate into all cell types in an adult, for which adult tissuespecific stem cells may, in some cases, not exist or may be difficult to isolate or propagate (1). For example, one potential CRT enabled by hPSCs is the treatment of spinal cord injury (SCI) with oligodendrocyte progenitor cells (OPCs). These hPSC-OPCs have recently advanced to a phase 2 clinical trial for the treatment of SCI (2) and are being considered for additional myelin-associated disorders in the central nervous system (CNS), including adrenoleukodystrophy, multiple sclerosis (3, 4), and radiation therapyinduced injury (5). In parallel, hPSC-derived midbrain dopaminergic (mDA) neurons are under consideration for Parkinsons disease therapy (6, 7).

The promise of hPSC-derived therapeutics such as hPSC-OPCs or mDA neurons motivates the development of manufacturing processes to accommodate the potential associated clinical need. For example, approximately 250,000 patients in the United States suffer from some form of SCI, with an estimated annual incidence of 15,000 new patients (8). Human clinical trials involving hPSC-OPCs have used dosages of 20 million cells per patient (9), such that the hypothetical demand would be over 1 trillion differentiated OPCs. It is therefore imperative to develop systems to enable discovery of efficient and scalable differentiation protocols for these therapies.

Differentiation protocols to direct hPSCs into functional OPCs (10, 11) have been developed to approximate the signaling environment at precise positions within the developing spinal cord. Positional identity of cells is guided patterning cues that form intersecting gradients along the dorsoventral axis, such as Sonic hedgehog (SHH), and rostrocaudal axis, such as retinoic acid (RA). In addition, certain cues are present along both axes, such as Wnts (1215). These signaling environments vary over time as the embryo develops (16, 17). However, translating this complex developmental biology to an in vitro culture requires optimization of a large combinatorial parameter space of signaling factor identities, doses, durations, dynamics, and combinations over many weeks to achieve efficient yield of the target cell type, and there remains open questions about the impact of cross-talk between patterning cues on the expression of cellular markers present in OPCs such as transcription factors Olig2 and Nkx2.2 (18). Strategies to derive OPCs and other potential CRTs from hPSCs have shown steady progress, especially with application of high-throughput screening technology (1921); however, current production systems for hPSC-derived CRTs involve two-dimensional (2D) culture formats that are challenging to scale (2228).

More recently, 3D culture systems have demonstrated strong potential for a larger scale and higher yield (29) of hPSC expansion and differentiation than 2D counterparts, as well as compatibility with good manufacturing practice (GMP) standards (3033). While high-throughput systems for screening 3D cell culture environments have been applied to basic biological studies of hPSC proliferation (34), we envision that this technology could additionally be applied toward systematically optimizing production strategies for CRTs to accelerate the pace of their discovery and development toward the clinic while simultaneously uncovering new interactions among signaling cues that affect cell fate. Here, we harness the powerful capabilities of a uniquely structured microculture platform (35, 36), to screen dosage, duration, dynamics, and combinations of several cellular signaling factors in 3D for hPSC differentiation (Fig. 1). The independent control of gel-encapsulated cells (on pillar chip) and media (in well chip) enables simultaneous media replenishment for more than 500 independent microcultures in a single chip. Furthermore, we use custom hPSC reporter cell lines (37) to enable live imaging of proliferation and differentiation of OPCs for over 80 days on the microculture chip. One thousand two hundred combinatorial culture conditions, amounting to 4800 independent samples, were screened while consuming less than 0.2% of the reagent volumes of a corresponding 96-well plate format. Furthermore, the robust dataset enabled statistical modeling to identify relative differentiation sensitivities to, and interactions between, various cell culture parameters in an unbiased manner. Last, we demonstrate the generalizability of the platform by applying it toward a screen for differentiation of tyrosine hydroxylaseexpressing dopaminergic neurons from hPSCs.

(A) A micropillar chip with cells suspended in a 3D hydrogel is stamped to a complementary microwell chip containing isolated media conditions to generate 532 independent microenvironments. One hundred nanoliters of hPSCs suspended in a hydrogel is automatically dispensed onto the micropillars, and 800 nl of media is automatically dispensed into the microwells by a robotic liquid handling robot programmed to dispense in custom patterns. The independent substrate for cells and media enables screens of combinations of soluble cues at various dosages and timings. Scale bar, 1 mm. (B) Timeline of exogenous signals for in vitro 3D OPC differentiation from hPSCs and anticipated cellular marker expression along various differentiation stages.

Initially, we assessed whether hPSCs could be dispensed in the microculture platform system uniformly and with high viability. Quantification of total, live, and dead cell counts across the microchip indicates uniform culture seeding and cell viability at the initiation of an experiment (fig. S1).

We then used a custom-made Nkx2.2-Cre H9 reporter line, which constitutively expresses DsRed protein but switches to green fluorescent protein (GFP) expression upon exposure to Cre recombinase, to longitudinally monitor proliferation and differentiation of hPSCs to Nkx2.2+ oligodendrocyte progenitors in 3D on the microchip platform. A small range of culture conditions from previously published protocols of OPC differentiation were selected for an initial, pilot differentiation experiment, and the GFP expression was quantified after 21 days of differentiation. Cell morphology changes accompanying neural lineage commitment and maturation were clearly observed at later stages in the 3D differentiation (movie S1 and fig. S2) as cultures were maintained and monitored for up to 80 days on the microchip. We then developed fluorescence image analysis pipelines for quantification of nuclear and cytoplasmic marker expression via immunocytochemistry for endpoint analyses at various times (fig. S3). Together, these results support the robust and long-term culture potential and cellular marker expression readout of this miniaturization methodology for hPSC differentiation screening.

hPSC seeding density. We first focused on parameters within the first week of 3D differentiation into OPCs (Fig. 2A). The importance of autocrine, paracrine, and juxtacrine signaling mechanisms among cells in many systems led us to anticipate that the density of cells at the start of differentiation could affect the early neural induction efficiency and, consequently, the efficiency of OPC differentiation. We therefore demonstrated the ability of this microculture platform to test a range of initial hPSC seeding densities on day 2 (fig. S1) and assessed the effect of seeding density on Olig2 expression. We observed notable differences in levels of cell-to-cell adhesion in hPSC cultures by day 0, 2 days after initial seeding (Fig. 2Bi). Then, after 15 days of differentiation, we observed a trend that lower hPSC seeding density, between 10 and 50 cells per pillar, increased OPC specification slightly (Fig. 2Bii).

(A) Timeline of key parameters in the early phase of OPC differentiation. (B) i. Bright-field images of 3D H9 microculture sites at day 0 seeded with varying cell densities and the immunocytochemistry images of Olig2 (red) expression at day 15. Scale bar, 100 microns. ii. Quantification of day 15 Olig2 expression with respect to seeding density and SAG dose. *P value < 0.05 using Tukeys Method for multiple comparisons. (C) i. Montage of 360 fluorescence confocal images representing 90 unique differentiation timelines on a single microchip stained for Hoechst (blue) and Olig2 (red) after 21 days of differentiation. ii. Trends in Olig2 expression at days 15 and 21 in various CHIR and RA concentrations and durations (short CHIR, days 0 to 1; long CHIR, days 0 to 3). Error bars represent 95% confidence intervals from four technical replicates.

Timing of SMAD inhibition relative to RA and Wnt signals. The formation of the neural tube in human development (12) results from cells in the epiblast being exposed to precisely timed developmental signals such as Wnt (38) and RA that then instruct neural subtype specification (39). This led us to hypothesize that the overall differentiation efficiency of hPSCs to OPCs in this 3D context in vitro would be sensitive to the timing at which RA and Wnt signals were introduced during neural induction. Therefore, we induced neuroectodermal differentiation of hPSCs via inhibition of bone morphogenetic protein (BMP) signaling using the dual SMAD inhibition approach (40), with LDN193189 (hereafter referred to as LDN) and SB431542 (hereafter referred to as SB), and tested a range of times (0, 2, and 4 days) at which RA and Wnt signals (by CHIR99021, hereafter referred to as CHIR) were introduced into the culture. We observed a strong correlation between early addition of RA/CHIR and OPC specification such that combined exposure of RA and CHIR signals with SMAD inhibition on day 0 resulted in up to sixfold higher Olig2 expression in some cases (fig. S4), potentially implicating an important role of synchronized exposure of RA and CHIR signals with SMAD inhibition for specifying Olig2+ progenitors. For subsequent experiments, we kept the timing of RA and CHIR addition at day 0 and evaluated how the dose and duration of these signals may affect Olig2+ specification.

Dose and duration of key signaling agonists. We examined the combinatorial and temporal effects of three signaling cues that form gradients across intersecting developmental axes in the neural tube to influence specification of oligodendrocyte progenitors: RA (present along the rostrocaudal axis of the CNS development), SHH (41) (a morphogen that patterns the dorsoventral axis of the developing CNS and is activated by smoothened agonist, hereafter referred to as SAG), and Wnt (present along both the rostrocaudal and dorsoventral axes). Because OPC specification is likely sensitive to the relative concentrations of these cues, for example, given the importance of morphogen gradients in oligodendrocyte differentiation in the developing neural tube (12), we assessed the Olig2 expression resulting from a full factorial combinatorial screen of these cues (fig. S5). Most notably, we observed positive correlations in Olig2 expression in response to increasing RA dose and increasing duration of CHIR exposure from days 0 to 4 of differentiation (Fig. 2C). Without CHIR, an increase in RA from 10 to 1000 nM resulted in a 10-fold increase of Olig2 expression by day 21. A similar 10-fold increase in Olig2 expression was observed at an RA concentration of 100 nM if CHIR was present for the first 3 days of differentiation (Fig. 2C). Analysis of variance (ANOVA) analysis revealed a strong effect size for RA when added early in the differentiation, as well as an interaction between RA dose and longer CHIR duration, in specifying Olig2+ cells in this 3D context (fig. S5), consistent with previous work conducted in 2D in vitro formats (19, 42).

In other developmental systems, the activity of the Wnt signaling pathway was observed to be biphasic (43), whereby activation of the pathway initially enhances cardiac development but later represses it. As this complex signaling profile has been applied to enhance cardiomyocyte differentiation protocols in vitro (44), we analogously investigated whether adding antagonists of key signaling pathways after pathway activation could further enhance the OPC differentiation efficiency by adjusting the dorsoventral and rostrocaudal positioning in vitro. Maintaining the 5 M CHIR for days 0 to 3 from the previous experiment, we used IWP-2 (an inhibitor of the Wnt pathway), GANTT61 (an antagonist of SHH signaling), and DAPT (a Notch pathway antagonist) (Fig. 3A) to inhibit endogenous autocrine/paracrine and/or basal signaling. We used a full factorial analysis of these cues to additionally probe for combinatorial interactions among the pathway inhibitors.

(A) Timing of addition for three inhibitory signaling cuesGANTT61, IWP-2, and DAPTin the OPC differentiation protocol. (B) i. Olig2+, Nkx2.2+, and the proportion of total Olig2+ that are Nkx2.2+/Olig2+ cells in at day 21 in response to full factorial combinations of selected novel signaling antagonists. ii. Immunocytochemistry images of costained Olig2 (red) and Nkx2.2 (green) cells. Scale bar, 100 m. Error bars represent 95% confidence intervals from four technical replicates.

To further refine the markers for OPC specification, we measured Nkx2.2 expression in addition to Olig2 and quantified the proportion of cells coexpressing both OPC markers. Most notably, a significant decrease in %Olig2 was observed in response to Notch inhibitor DAPT across all conditions tested (Fig. 3Bi). The same trend was not observed with respect to %Nkx2.2. This result could point to a role for Notch signaling in maintaining or promoting specification of Olig2+ progenitorsa hypothesis not previously examined to our knowledgeand serves as preliminary evidence to test Notch agonists such as DLL-4 in follow-up studies of OPC optimization. This effect may be mediated by an interaction with the SHH pathway (45).

A slight increase in %Olig2+ cells was detected with increasing Wnt inhibitor IWP-2 dose when no SHH inhibitor GANTT61 was present, as was a slight increase in %Nkx2.2+ cells as a function of increasing IWP-2 and GANTT61 dose, pointing to a potential interaction between these two cues in inducing Nkx2.2 expression. The highest proportion of Olig2+Nkx2.2+ cells was observed at the highest IWP-2 and GANTT61 doses and was not influenced by DAPT exposure (Fig. 3Bii). As CHIR was present between days 0 and 3 in the differentiation, it seems that the role of Wnt signaling changes during the 21-day differentiation window of hPSCs to OPCs in that initially (days 0 to 3) it promotes OPC differentiation but shifts to an inhibitory role at later stages (days 4 to 21). To examine the extent of reproducibility of these findings, we tested the effect of temporal modulation of Wnt signals in a human induced pluripotent stem cell (hiPSC) line, TCTF, and found that the general trend of activation followed by inactivation of Wnt signaling would increase the proportion of Olig2+ cells at day 21 (fig. S6).

Although the levels of key signaling cues may vary temporally within the natural developmental environment of certain target cell types, such as within the neural tube where a dynamic SHH gradient along the dorsoventral axis patterns pMN development (16, 17), the dosage of signaling cues in the media for in vitro stem cell differentiation protocols is often applied at a constant level throughout the culture period. On the basis of this discrepancy, we applied the micropillar/microwell chip to screen through numerous temporal profiles of SAG, as well as RA due to its analogous role along the rostrocaudal axis during spinal cord development, by dividing the signal window into early and late stages that were dosed independently to form constant, increasing, and decreasing dose profiles over time (Fig. 4A). To gain additional insights into OPC marker expression, we measured Tuj1 expression and calculated the proportion of Olig2+ cells that coexpressed Tuj1 to potentially identify any modulators of the balance between Olig2+ cells that proceed down a motor neuron fate (which are both Olig2+ and Tuj1+) versus an oligodendrocyte fate (Olig2+/Nkx2.2+).

(A) Timeline of early and late windows for RA and SAG exposure. (B) i. Hierarchical cluster analysis of standardized (z score) phenotypic responses to temporal changes in RA and SAG dose during OPC differentiation. ii. Representative immunocytochemistry images of each major category of endpoint population phenotype mix of Olig2 (red), Nkx2.2 (green), and Tuj1 (orange) expression. Scale bar, 100 m. iii. Olig2, Nkx2.2, and coexpression of Olig2+Nkx2.2+ and Olig2+Tuj1+ at day 15 in response to time-varying doses of SAG. Error bars represent 95% confidence intervals from four technical replicates. *P value < 0.05.

To consider all measured phenotypes simultaneously, we applied a hierarchical cluster analysis from which we were able to identify several patterns. A broad range of endpoint phenotype proportions of Olig2, Nkx2.2, and Tuj1 was found to result from varying the temporal dosing of only two signaling cues, RA and SAG, pointing to a very fine sensitivity to temporal changes in signal exposure in these populations. Four categories of the endpoint marker expression profiles were created to further interpret the cluster analysis. Categories 1 and 2 are composed of phenotypes ranking low on OPC progenitor fate (low Olig2 and/or Nkx2.2 expression), all of which shared the low dosing of RA at 0.1 M between days 2 and 21 of the differentiation, further emphasizing the strong impact of RA on OPC yield. In contrast, category 3composed of the highest Olig2 and Nkx2.2 expression as well as Olig2+Nkx2.2+ proportioncorrelated with the highest dose of early SAG but had negligible differences across doses of late SAG (Fig. 4Biii, and fig. S7). Last, category 4 points to a biphasic relationship of Nkx2.2 expression as a function of RA dosage, where a high dose of RA of 1 M in the late stage of differentiation resulted in lower Nkx2.2 expression (fig. S8) compared with a consistent RA of 0.5 M throughout the entire differentiation. It appears that Olig2 and Nkx2.2 undergo maxima under different RA dosage profiles (fig. S8), and therefore, the use of coexpressing Olig2+Nkx2.2+ cells as the main metric when optimizing OPC differentiation may be most suitable.

We sought a comprehensive, yet concise, analysis to describe individual and combinatorial effects of all 12 culture parameters (e.g., signal agonist and antagonist dosages and timings) on the results of the more than 1000 unique differentiation conditions involved in this study. To this end, we fit generalized linear models to correlate the expression and coexpression of Olig2, Nxk2.2, and Tuj1 to individual input parameters within the 12 culture parameters involved in this study, and the 132 pairwise interactions between them. First, we identified significant parameters of interest for each phenotype measured using a factorial ANOVA (fig. S9). After applying a Benjamini and Hochberg false discovery rate correction for multiple comparisons (46), we fit an ordinary least squares model of the statistically significant terms to the phenotype of interest. The parameter coefficients were analyzed as a measure of relative influence on the expression of a certain endpoint phenotype, such as Olig2+Nkx2.2+ cells, and could be interpreted as a sensitivity analysis of key parameters on the OPC specification process. The most significant parameters were then sorted by their effect magnitude (Fig. 5B).

(A) Identification of statistically significant culture parameters using a factorial ANOVA of all single and pairwise effects on Nkx2.2 expression subject to the Benjamini and Hochberg false discovery rate (B&H FDR) correction. (B) Effect magnitude of significant culture parameters for i. Nkx2.2 expression, ii. Olig2 expression, iii. and coexpression of Olig2 and Nkx2.2. (C) i. Diagram summarizing results and effect magnitude of significant culture parameters for Olig2 and Nkx2.2 coexpression within the Olig2+ population and ii. effect magnitude of significant culture parameters for Olig2 and Tuj1 coexpression within the Olig2+ population.

RA, a rostrocaudal patterning cue, was among the most impactful parameters in this study for Olig2 and Nkx2.2 expression (Fig. 5Bi and ii). In particular, a high RA dose (1 M) early in the differentiation (days 0 and 1) emerged as the most influential culture parameter in the acquisition of OPC fate (coexpression of Olig2 and Nkx2.2) (Fig. 5Bi to iii). In addition, the dose of SAG from days 4 to 10 of differentiation exerted a markedly more significant impact on OPC fate induction than from days 10 to 21 of differentiation, in line with the previous analysis (Fig. 4). IWP-2 and GANT were observed to correlate positively with coexpression of Olig2 and Nkx2.2 as well. Furthermore, this analysis identified two cases of culture parameters interacting in a synergistic manner to promote OPC differentiation. First, higher doses of RA during days 0 to 2 followed by SAG during days 4 to 10 were found to promote higher Nkx2.2 expression. In addition, longer CHIR duration (from days 0 to 4) along with higher GANT dose promoted coexpression of Nkx2.2 and Olig2.

We created a new differentiation protocol from the parameters isolated in this screen to have the most influence in specifying Olig2+Nkx2.2+ progenitors (Fig. 5Biii) and carried out the differentiation into the later stages of OPC maturation in a larger-scale format to assess the ability of this optimized protocol to create mature oligodendrocytes. The protocol was able to produce platelet-derived growth factor receptor (PDGFR)expressing cells by day 60 across multiple hPSC lines, as well as O4-expressing cells by day 75 and myelin basic protein (MBP) expressing cells and myelination ability at day 100 (fig. S10).

The OPC screening identified new conditions that affect cell differentiation, and we then sought to demonstrate the generalizability of this approach by conducting a different study. Specifically, we screened 90 unique hPSC differentiation protocols for tyrosine hydroxylase+ mDA neurons (Fig. 6). Exposure of CHIR was divided into three periods (early, middle, and late), and dosage for each period was varied independently. This screening strategy uncovered a key window of CHIR competence between days 3 and 7 (early), a negligible effect of CHIR between days 8 and 11 (middle), and an inhibitory effect of CHIR between days 12 and 25 (late) of mDA differentiation. These data further illustrate the existence of biphasic signaling activity during the differentiation process and underscore the need to improve the temporal dosing of several signaling agonists across a range of hPSC-derived CRTs.

(A) Timeline of small-molecule addition for differentiation of mDA neurons from hPSCs. (B) Montage of 90 unique differentiation timeline to test temporal profiles of CHIR dose stained for tyrosine hydroxylase (TH) and Tuj1. Scale bar, 1 mm. (C) Immunocytochemistry images of i. low, ii. medium, and ii. high proportions of TH+ (yellow) neurons (red) dependent on the temporal profile of CHIR exposure. Scale bar, 100 m.

The clinical emergence of several cell-based therapy candidates (47) is encouraging for human diseases/disorders that currently have no effective small molecule or biologic-based therapy. As research and development into CRT candidates continues to progress, cell production has emerged as a bottleneckas delivery vectors recently have in gene therapyand improved tools will be necessary to enable higher quality and yield in cell manufacturing. Although previous studies have reported ~90% hPSC differentiation efficiency into Olig2+ progenitors using 2D culture formats (19), the 2D culture format constrains the space in which cells can expand to the surface area of the culture plate that limits the overall cell yield that can be produced. The adoption of scalable 3D culture formats, which have demonstrated the ability to produce up to fivefold higher quantities of cells per culture volume, shows promise in surpassing limits of 2D cell expansion (2933) and could result in a higher overall production quantity of target cells even if differentiation efficiencies were lower than what has been reported in 2D. Therefore, the 3D screening and analysis strategy presented here is relevant for numerous emerging CRT candidates for which conversion of a stem or progenitor cell, such as a hPSCs (48), to a therapeutically relevant cell type requires searching through a large in vitro design space of doses, durations, dynamics, and combinations of signaling cues over several weeks of culture.

Notably, to emulate a ubiquitous and naturally occurring phenomenon in organismal development (16, 49), we dynamically varied key signaling cues in our screening strategy, tuning dosage over time. These analyses revealed new biological insights into the dynamic process by which cell competence to signals and fate are progressively specified (50). For example, by applying this platform to screen through several dynamic signaling levels simultaneously, we observed that the differentiation toward Nkx2.2+ progenitors is very sensitive to the dose of RA between days 0 and 1 and the dose of SAG between days 4 and 10. After these respective time windows, the effect of each respective signal in producing Nkx2.2+ progenitors is decreased, potentially pointing to a decrease in cellular competence to each of these signals over the course of OPC development. These cases of stage-specific responses to signaling cues, revealed by our screening platform, create a new dimension for future optimization of cell production.

To effectively navigate this enormous parameter space across doses, durations, dynamics, and combinations of signaling cues and resulting differentiation outcomes, we developed a robust sensitivity analysis strategy that can rank effect sizes to reveal which parameters should be the focus of optimization to modulate expression of target markers of interest (49) and, by contrast, which parameters exert minimal impact and can thus be neglected. For example, titration of RA dose will exert a significantly higher impact on differentiation efficiency than several other culture parameters combined. Furthermore, insights from this study could reduce the necessary quantity of SHH agonist by more than 50% to achieve similar levels of OPC differentiation. As these cell production processes translate from bench scale to industrial scale, awareness of key parameters that influence critical quality attributes (18) of the cell therapy product (such as expression of specific cellular markers) will be a necessary step in reliably producing these therapeutic cell types at scale for the clinic (51).

The wealth of combinatorial and temporal signaling patterns identified in this study can be analyzed in the context of CNS development as well. We observed a potential case of biphasic activity for the Wnt signaling pathway as both activation and inhibition appeared to increase expression of OPC markers Nkx2.2 and Olig2. In particular, this effect was seen with initial Wnt activation by CHIR during days 0 to 3 of OPC differentiation followed by inhibition by IWP-2 during days 4 to 21 of OPC differentiation. The Wnt pathway has shown stage-specific activity in cardiac and hematopoietic development (43, 44), which may thus be a conserved feature across several developmental systems. Wnt signals play an important role in the gastrulation of the embryo to form the primitive streak (38), yet in the subsequent stages of spinal cord development, Wnt signals induce a dorsalizing effect (52), whereas oligodendrocytes originate from the motor neuron domain on the ventral side. Therefore, suppressing endogenous Wnt signals in vitro after initial activation of Wnt may better recapitulate the natural developmental signaling environment of developing oligodendrocytes. Alternatively, as Wnt signals also play a role in rostrocaudal patterning of the CNS, these insights may further point toward a rostrocaudal region of the CNS during this developmental window that is optimal to recapitulate in vitro for OPC production. The oligodendrocytes created through this protocol, which expressed OTX2 at day 10 (fig. S2C), may resemble OPCs in the midbrain/hindbrain region. It is conceivable that exposure to the Wnt antagonist, IWP-2, induced a position rostral to the spinal cord during the differentiation window. This biphasic Wnt trend was seen again in our analysis of differentiation of mDA neurons, underscoring that stage-specific responses may be a conserved feature across several differentiation processes aiming to recapitulate a precise cellular position across several axes of patterning signals during natural development.

Furthermore, the statistical model identified an interaction between RA and SAG (an SHH agonist) in the early differentiation windows for specifying Nkx2.2+ progenitors (Fig. 5B), which has not been previously reported to our knowledge. In the developing CNS, RA signaling influences rostrocaudal positional identity, whereas SHH signaling specifies dorsoventral positional identity. Therefore, this statistical interaction found in the screen may represent intracellular cross-talk between the RA and SHH signaling pathways to integrate both patterning dimensions into Nkx2.2+ progenitor identity. This finding builds on what is known about RA and SHH signals for Olig2+ progenitor development in the spinal cord (53, 54).

Additionally, the 3D context of this screening platform enables high-throughput investigation into neurodevelopmental model systems that can offer unique perspectives beyond what is capable in 2D screening platforms, for example, by recapitulating cell-to-cell interactions, cytoskeletal arrangement, and multicellular patterning in 3D. The lumen structures that were observed during the neural induction period (fig. S2B and movie S1) in response to caudalizing conditions (high Wnt and RA) could be the basis of future organoid screening strategies to probe early multicellular arrangement and the effect of lumen size and shape on cell fate determination at various positions along the rostrocaudal and dorsoventral axes.

In conclusion, we demonstrate the versatile capabilities of a unique microculture platform for 3D differentiation screening and optimization of hPSC-derived cell therapies, whereby 1200 unique OPC differentiation timelines, and a total of over 4800 independent samples, were investigated using 0.2% of the reagent volumes required in a standard 96-well plate format. The dense dataset enabled subsequent statistical modeling for empirical optimization of the differentiation process and identified differential sensitivities to various culture parameters across time. These insights are important in developing strong process knowledge for manufacturing stem cell therapeutics as they continue to emerge in the clinic, and therefore, such screening strategies may accelerate the pace of discovery and development. Simultaneously, this combinatorial 3D hPSC differentiation screens may provide new insights on the basic biology of human development.

Human embryonic stem cells (H9s: National Institutes of Health Stem Cell Registry no. 0062) and hiPSCs (TCTFs: 8FLVY6C2, a gift from S. Li) were subcultured in monolayer format on a layer of 1% Matrigel and maintained in Essential 8 medium during expansion. At 80% confluency, H9s were passaged using Versene solution and replated at a 1:8 split.

H9s were dissociated into single cells using Accutase solution and resuspended in Essential 8 medium containing 10 M Y-27632 (ROCK Inhibitor). H9s were counted and resuspended at defined densities in 50% Matrigel solution on ice. While chilled, 100 nl of H9s in 50% Matrigel solution was deposited onto the micropillars at a density of 100 cells per pillar, unless otherwise noted, using a custom robotic liquid handling program and then incubated at 37C for 20 min to promote gelation of 3D cultures. The micropillar chip was then inverted and placed into a fresh microwell chip containing cell culture media (table S1). All liquid dispensing into the microculture platform was performed with a DIGILAB OmniGrid Micro liquid handler with customized programs for deposition patterns. Between days 2 and 0, cells were kept in E8 media supplemented with 10 M ROCK Inhibitor. Between days 0 and 10, cells were kept in differentiation media made of a base of 50% Dulbeccos Modified Eagles MediumF12, 50% Neurobasal, 0.5% penicillin/streptomycin (pen/strep), 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. Between days 10 and 21, cells were kept in differentiation media made of a base of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. After day 21, OPCs were transitioned to maturation media consisting of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, 1:50 N2 supplement, insulin-like growth factor 1 (10 ng/ml), platelet-derived growth factor (PDGF)AA (10 ng/ml), NT-3 (10 ng/ml), and insulin (25 g/ml). Media were changed daily by transferring the micropillar chip into a microwell chip containing fresh media every other day using a custom-made mechanical Chip Swapper for consistent transfer. Technical replicates included two different dispensing patterns to average out positional effects across the microchip.

At the endpoint of the experiment, the micropillar chip was carefully removed from the microwell chip and placed in new microwell chip containing calcein AM, ethidium homodimer, and Hoechst diluted in sterile phosphate-buffered saline (PBS) (dilution details in table S1). The micropillar chip was incubated for 20 min and then transferred to a new microwell chip containing PBS, and individual microenvironments were imaged using fluorescence microscopy.

At the endpoint of the experiment, the micropillar chip was carefully removed from the wellchip and placed into a bath of 4% paraformaldehyde for 15 min to fix cell cultures. Then, the micropillar chip was washed twice in PBS for 5 min each and placed into a bath of 0.25% Triton X-100 + 5% donkey serum in PBS for 10 min to permeabilize cells. After permeabilization, the micropillar chip was washed five times in 5% donkey serum for 5 min each, transferred to a wellchip containing primary antibodies of interest diluted in PBS + donkey serum (dilution details in table S1), and stored overnight at 4C. After primary staining, the micropillar chip was washed twice in PBS for 5 min each, placed into a microwell chip containing the corresponding secondary antibodies (dilution details in table S1), and incubated at 37C for 2 hours. After secondary staining, the micropillar chip was washed twice in PBS for 5 min each and placed into a wellchip containing PBS; individual microenvironments were imaged using fluorescence confocal microscopy.

Stained micropillar chips were sealed with a polypropylene film (GeneMate T-2452-1) and imaged with a 20 objective using a Perkin Elmer Opera Phenix automated confocal fluorescence microscope available in the High-Throughput Screening Facility at University of California, Berkeley. Laser exposure time and power were kept constant for a fluorescence channel within an imaging set. Images were scored for marker expression depending on nuclear or cytoplasmic localization (fig. S3).

Fixed cultures on micropillars at day 15 were stained with 4,6-diamidino-2-phenylindole (DAPI) and imaged using an upright Olympus BX51WI microscope (Olympus Corporation) equipped with swept field confocal technology (Bruker) and a Ti:sapphire two-photon Chameleon Ultra II laser (Coherent) was used. The two-photon laser was set to 405 nm, and images were captured using an electron multiplying charge-coupled device camera (Photometrics). Prairie View Software (v. 5.3 U3, Bruker) was used to acquire images, and ImageJ software was used to create a video of the z-series.

Quantified image data were then imported into Python for statistical data analysis (55) and visualization. For comparisons between datasets acquired across different experimental sessions, raw data were scaled and centered by z score, and descriptive statistics were calculated from four technical replicates. Error bars represent 95% confidence intervals, unless otherwise specified. For the hierarchical cluster model, the Euclidean distance was used to measure pairwise distance between each observation, and the unweighted pair group method with arithmetic mean (UPGMA) algorithm was used to calculate the linkage pattern. A Benjamini and Hochberg false discovery rate correction was applied as needed to correct for multiple comparisons. Code is available upon request.

Acknowledgments: We thank M. West of the High-Throughput Screening Facility (HTSF) at UC Berkeley and E. Granlund of the College of Chemistry machine shop for machining custom parts. In addition, we are grateful to G. Rodrigues, M. Adil, and J. Zimmermann for participating in the discussions on the work. Funding: This research was supported by the California Institute for Regenerative Medicine (DISC-08982) and the NIH (R01-ES020903) and Instrumentation Grant (S10OD021828) that provided the Perkin Elmer Opera Phenix microscope. R.M. was supported in part by an NSF Graduate Research Fellowship. Author contributions: R.M., D.S.C., and D.V.S. conceived various parts of the project and supervised the study. R.M. designed the experiments and managed the project workflows. X.B. created Nkx2.2-Cre H9 reporter lines. R.M., E.T., and E.C. performed the experiments. R.M. conducted statistical modeling, and A.M. aided in statistical testing. R.M., D.S.C., and D.V.S. analyzed and interpreted the data. R.M. wrote the manuscript with revisions from J.S.D., D.S.C., and D.V.S. Competing interests: R.M., D.S.C., and D.V.S. are inventors on a U.S. patent pending related to this work filed by the University of California, Berkeley (PCT/US2020/029553, filed on 23 April 2020). D.V.S. is the inventor on two U.S. patent pendings related to this work filed by the University of California, Berkeley (PCT/US2016/055362, filed on 4 October 2016; no. PCT/US2016/055361, filed on 5 October 2015). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates - Science Advances

Immatics Extends Cell Therapy Manufacturing Collaboration with UTHealth – GlobeNewswire

Houston, Texas, Aug. 06, 2020 (GLOBE NEWSWIRE) --

Houston, Texas, August 6, 2020 Immatics N.V. (NASDAQ: IMTX; Immatics), a clinical-stage biopharmaceutical company active in the discovery and development of T cell redirecting cancer immunotherapies, today announced the extension of its cell therapy manufacturing collaboration with The University of Texas Health Science Center at Houston (UTHealth), in Houston, Texas. The continued collaboration grants Immatics access to UTHealths state-of-the-art cGMP manufacturing infrastructure at the Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory, enabling continued production and supply of Immatics specialized, cell-based product candidates for testing in multiple clinical trials. Maximum capacity of the facility is anticipated at 48 ACTengine T cell products per month. The new agreement will run until the end of 2024. Under the agreement, UTHealth will provide Immatics with exclusive access to three cGMP suites and support areas for the manufacturing of various Adoptive Cell Therapy (ACT) products. Therapeutic T cell production will be carried out by Immatics manufacturing personnel and will be supported by a UTHealth-Immatics joint quality team.

Steffen Walter, Ph.D., Chief Technology Officer at Immatics, commented: During the last five years, we have established a strong and productive partnership with UTHealth that has enabled the initiation of four ongoing clinical trials. As we remain focused on the development of our clinical pipeline, this extension of our collaboration with UTHealth will fulfill Immatics manufacturing needs for our early-stage ACT clinical programs for the next four years. Being able to rely on a partner with profound cell therapy expertise who is familiar with our technologies and can support cGMP cell therapy production is critical to ensuring the advancement of our clinical trials. We look forward to continuing this fruitful collaboration with the experts at UTHealth.

Fabio Triolo, D.d.R., M.Phil., Ph.D., The Clare A. Glassell Distinguished Chair and Director of the Cellular Therapy Core at UTHealth, added: Signing the extended contract with Immatics fits into our strategy at UTHealth of supporting the development of new treatments for patients in need. We therefore look forward to continuing our collaboration and further leveraging the potential of our manufacturing capabilities.

About Immatics ACT ProgramsACTengine is a personalized approach in which the patients own T cells are genetically modified to express a novel proprietary TCR cognate to one of Immatics proprietary cancer targets which are then reinfused back into the patient. Immatics latest proprietary ACTengine manufacturing processes are designed to generate cell product candidates within a short six day manufacturing window and to deliver highly proliferative T cells, with the capability to infiltrate the patients tumor and function in a challenging solid tumor microenvironment. The process is designed to rapidly produce younger, better-persisting T cells capable of serial killing tumor cells in vitro. Immatics is further advancing the ACT concept beyond individualized manufacturing with its product class ACTallo which is being developed to generate off-the-shelf cellular therapies.

More information on the clinical trials can be found at the following links: https://immatics.com/clinical-programs/ and https://clinicaltrials.gov/.

- ENDS -Notes to Editors

About ImmaticsImmatics combines the discovery of true targets for cancer immunotherapies with the development of the right T cell receptors with the goal of enabling a robust and specific T cell response against these targets. This deep know-how is the foundation for our pipeline of Adoptive Cell Therapies and TCR Bispecifics as well as our partnerships with global leaders in the pharmaceutical industry. We are committed to delivering the power of T cells and to unlocking new avenues for patients in their fight against cancer.

For regular updates about Immatics, visit http://www.immatics.com. You can also follow us on Twitter and LinkedIn.

About UTHealthEstablished in 1972 by The University of Texas System Board of Regents, The University of Texas Health Science Center at Houston (UTHealth) is Houstons Health University and Texas resource for health care education, innovation, scientific discovery and excellence in patient care. The most comprehensive academic health center in the UT System and the U.S. Gulf Coast region, UTHealth is home to Jane and Robert Cizik School of Nursing, John P. and Kathrine G. McGovern Medical School and schools of biomedical informatics, biomedical sciences, dentistry and public health. UTHealth includes The University of Texas Harris County Psychiatric Center, as well as the growing clinical practices UT Physicians, UT Dentists and UT Health Services. The universitys primary teaching hospitals are Memorial Hermann-Texas Medical Center, Childrens Memorial Hermann Hospital and Harris Health Lyndon B. Johnson Hospital. For more information, visit http://www.uth.edu.

About the Evelyn H. Griffin Stem Cell Therapeutics Research LaboratoryThe Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory, which is part of the Cellular Therapy Core at UTHealth, has been Immatics manufacturing partner since 2015. The site is a U.S. Food and Drug Administration (FDA)-registered and inspected cGMP facility that has received accreditation from the Foundation for Accreditation of Cellular Therapy (FACT) as well as certification from the Clinical Laboratory Improvement Amendment (CLIA) and the College of American Pathologists (CAP).

Forward-Looking StatementsCertain statements in this press release may be considered forward-looking statements. Forward-looking statements generally relate to future events or Immatics future financial or operating performance. For example, statements concerning the timing of product candidates and Immatics focus on partnerships to advance its strategy are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as may, should, expect, intend, will, estimate, anticipate, believe, predict, potential or continue, or the negatives of these terms or variations of them or similar terminology. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Immatics and its management, are inherently uncertain. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, but are not limited to, various factors beyond management's control including general economic conditions and other risks, uncertainties and factors set forth in filings with the Securities and Exchange Commission (SEC). Nothing in this presentation should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements, which speak only as of the date they are made. Immatics undertakes no duty to update these forward-looking statements.

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Immatics Extends Cell Therapy Manufacturing Collaboration with UTHealth - GlobeNewswire

Contract Manufacturing Services market for stem cells is expected to be worth over USD 2.5 billion by 2030, claims Roots Analysis – Market Research…

Driven by a robust and growing pipeline of stem cell therapies, the demand for development and manufacturing services for such advanced product candidates is anticipated to increase beyond the capabilities of innovator companies alone

Roots Analysis has announced the addition of the Stem Cell Contract Manufacturing Market, 2019-2030 report to its list of offerings.

Owing to a highly regulated production environment and the need for state-of-the-art technologies and equipment, it is difficult for innovators to establish in-house expertise for the large-scale manufacturing of stem cell therapies. As a result, stem cell therapy developers are increasingly relying on contract manufacturing organizations (CMOs) for their product development and manufacturing needs.

To order this 300+ page report, which features 120+ figures and 145+ tables, please visit this link

Over 80 CMOs presently claim to provide manufacturing services for stem cells therapiesThe market landscape is fragmented, featuring a mix of companies of all sizes; however, small and mid-sized companies represent 70% of the overall number of industry stakeholders. It is worth highlighting that over 50% of the CMOs claim to be capable of accommodating both clinical and commercial scales of operation.

100+ strategic alliances have been inked since 2015In fact, nearly 60% of the abovementioned deals were established post 2016. Majority of these agreements were observed to be focused on the manufacturing of various types of stem cells. It is worth highlighting that the maximum number of partnerships related to stem cell therapies were reported in 2018.

More than 80,000+ patients were reported to have been enrolled in stem cell therapy related trials, since 2010As a result, the manufacturing demand for such therapies can be anticipated to grow significantly over the next decade. The report features detailed projections of the future clinical and commercial demand for stem cell manufacturing, based on parameters, such as target patient population, dosing frequency, dose strength, source of stem cells, type of stem cells and key geographies.

Currently, there are more than 100 facilities dedicated to stem cell manufacturingThe maximum share of the installed capacity belongs to large (more than 1,000 employees) and very large (more than 5,000 employees) companies. The report provides a detailed capacity analysis, taking into consideration the reported manufacturing capacities of industry stakeholders, and offering estimates on the distribution of the global contract manufacturing capacity for stem cell therapies, by company size, scale of operation and geography.

By 2030, North America and Europe are anticipated to capture over 70% of the market shareOverall, the market is anticipated to witness an annualized growth rate of more than 20% over the next decade. In the long-term, the opportunity is expected to be well distributed across key stakeholder companies, which offer services for a diverse range of allogenic and autologous stem cell therapies.

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The USD 2.5 billion (by 2030) financial opportunity within the stem cells contract manufacturing market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom the contract manufacturing opportunity related to stem cell therapies can be expected to witness substantial growth due to the rising demand for regenerative medicine across a number of therapeutic areas. The report includes detailed transcripts of discussions held with the following experts:

The research covers detailed profiles of key players (illustrative list provided below) from across key global markets (North America, Europe and Asia-Pacific); each profile provides an overview of the company, information on its service portfolio, manufacturing facilities, financial performance (if available), details on recent developments, as well as an informed future outlook.

For additional details, please visit https://www.rootsanalysis.com/reports/view_document/stem-cell-therapy-contract-manufacturing-market-2019-2030/271.html

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Contract Manufacturing Services market for stem cells is expected to be worth over USD 2.5 billion by 2030, claims Roots Analysis - Market Research...

In Depth Analysis and Survey of COVID-19 Pandemic Impact on Global Cancer Stem Cell Market Report 2020 Key Players Thermo Fisher Scientific Inc.,…

Rising number of corona virus cases has impacted numerous lives and led to numerous fatalities, and has affected the overall economic structure globally. The Cancer Stem Cell has analyzed and published the latest report on the global Cancer Stem Cell market. Change in the market has affected the global platform. Along with the Cancer Stem Cell market, numerous other markets are also facing similar situations. This has led to the downfall of numerous businesses, because of the widespread increase of the number of cases across the globe.href=mailto:nicolas.shaw@cognitivemarketresearch.com>nicolas.shaw@cognitivemarketresearch.com or call us on +1-312-376-8303.

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The major players in the Cancer Stem Cell market are Thermo Fisher Scientific Inc., AbbVie Inc., Merck KGaA, Bionomics, Lonza, Stemline Therapeutics Inc., Miltenyi Biotec, PromoCell GmbH, MacroGenics Inc., OncoMed Pharmaceuticals Inc., Irvine Scientific, STEMCELL Technologies Inc., Sino Biological Inc., BIOTIME Inc. . Some of the players have adopted new strategies to sustain their position in the Cancer Stem Cell market. A detailed research study is done on the each of the segments, and is provided in Cancer Stem Cell market report. Based on the performance of the Cancer Stem Cell market in various regions, a detailed study of the Cancer Stem Cell market is also analyzed and covered in the study.

Report Scope:Some of the key types analyzed in this report are as follows: Cell Culturing, Cell Separation, Cell Analysis, Molecular Analysis, Others

Some of the key applications as follow: Stem Cell Based Cancer Therapy, Targeted CSCs

Following are the major key players: Thermo Fisher Scientific Inc., AbbVie Inc., Merck KGaA, Bionomics, Lonza, Stemline Therapeutics Inc., Miltenyi Biotec, PromoCell GmbH, MacroGenics Inc., OncoMed Pharmaceuticals Inc., Irvine Scientific, STEMCELL Technologies Inc., Sino Biological Inc., BIOTIME Inc.

An in-depth analysis of the Cancer Stem Cell market is covered and included in the research study. The study covers an updated and a detailed analysis of the Cancer Stem Cell market. It also provides the statistical information of the Cancer Stem Cell market. The study of the report consists of the detailed definition of the market or the overview of the Cancer Stem Cell market. Furthermore, it also provides detailed information for the target audience dealing with or operating in this market is explained in the next section of the report.

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The report also provides detailed information on the research methodologies, which are used for the analysis of the Cancer Stem Cell market. The methods are covered in detail in this section of the report. For the analysis of the market, several tools are used for the extraction of the market numbers. Among the several tools, primary and secondary research studies were also incorporated for the research study. These were further analyzed and validated by the market experts, to increase precision and make the data more reliable.

Moreover, the report also highlights and provides a detailed analysis of the drivers, restrains, opportunities, and challenges of the Cancer Stem Cell market. This section of Cancer Stem Cell market also covers the updated information, in accordance with the present situation of the market.

According to the estimation and the analysis of the market, the Cancer Stem Cell market is likely to have some major changes in the estimated forecasts period. Moreover, these changes can be attributed to the changes due to economic and trading conditions across the globe. Moreover, several market players operating in the Cancer Stem Cell market will have to strategically change their business strategies in order to survive in the market.

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Reasons for Buying this Cancer Stem Cell Report1. Cancer Stem Cell market advertise report helps with understanding the Basic product segments alongside likewise their potential future.2. This global Cancer Stem Cell report offers pin-point evaluation for changing competitive dynamics.3. The Cancer Stem Cell market supplies pin point analysis of changing competition dynamics and keeps you in front of competitors4. Original images and illustrated a SWOT evaluation of large segments supplied by the Cancer Stem Cell market.5. This report supplies a forward-looking perspective on different driving factors or controlling Cancer Stem Cell market gain.6. This report assists to make wise business choices using whole insights of the Cancer Stem Cell and also from creating a comprehensive evaluation of market sections.Note In order to provide more accurate market forecast, all our reports will be updated before delivery by considering the impact of COVID-19.

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About Us: Cognitive Market Research is one of the finest and most efficient Market Research and Consulting firm. The company strives to provide research studies which include syndicate research, customized research, round the clock assistance service, monthly subscription services, and consulting services to our clients. We focus on making sure that based on our reports, our clients are enabled to make most vital business decisions in easiest and yet effective way. Hence, we are committed to delivering them outcomes from market intelligence studies which are based on relevant and fact-based research across the global market.

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In Depth Analysis and Survey of COVID-19 Pandemic Impact on Global Cancer Stem Cell Market Report 2020 Key Players Thermo Fisher Scientific Inc.,...

Tafasitamab Combination Approved for Adults With R/R DLBCL – AJMC.com Managed Markets Network

On July 31, FDA approved tafasitamab-cxix to be used in combination with lenalidomide for second-line treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), meeting the needs of patients who are not eligible for an autologous stem cell transplant.

Tafasitamab, to be sold as Monjuvi by MorphoSys and Incyte, is a humanized Fc-modified cytolytic CD19 monoclonal antibody being studied in several B-cell malignancies. As described in the journal Blood, the treatment uses Xencors proprietary Xmab technology, which deploys a different technique to boost affinity for the antigen and make various receptors especially capable of binding to it. In 2018, authors in Annals of Oncology described how this sets off particularly effective processes that target cancer cells and regulate cell death.

Approval was based on phase 2 results for 80 patients in the L-MIND trial, which reported an update May 2019 at the American Society of Clinical Oncology, with final results published last month in The Lancet. Results submitted to FDA showed an overall response rate of 55%, including a compete response rate of 37% and a partial response rate of 18%. Median duration of response was 21.7 months. Common adverse events included neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.

Among non-Hodgkin lymphomas, DLBCL is the most common subtype, accounting for 22% of cases in the United States and 40% worldwide, with about 18,000 US cases per year. People are at higher risk if they have HIV, an autoimmune disease, or if they have had an organ transplant. More common in older people, DLBCL can be very aggressive. Although well-known treatments have been developed, there are gapsand a notable one is when DLBCL cannot be kept in remission after chemotherapy but the patient is not eligible for an autologous stem cell transplant. Some of these patients have had chimeric antigen receptor (CAR) T-cell therapy, but this process is costly with significant side effects.

The FDA approval of Monjuvi in combination with lenalidomide helps address an urgent unmet medical need for patients with relapsed or refractory DLBCL in the United States, Herv Hoppenot, CEO of Incyte, said in a statement. At Incyte we are committed to advancing patient care and are proud to bring this new and much-needed targeted therapeutic option to appropriate patients and the clinical community.

FDA had previously granted the combination Fast Track and Breakthrough Therapy Designation in this indication.

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Tafasitamab Combination Approved for Adults With R/R DLBCL - AJMC.com Managed Markets Network

Celularity announces the activation of first California Clinical Trial Site following CIRM Grant Award to Advance Treatments for COVID-19 – PRNewswire

FLORHAM PARK, N.J., Aug. 5, 2020 /PRNewswire/ --Celularity today announced that it has been awarded a $750,000 COVID-19 Project grant by the California Institute for Regenerative Medicine (CIRM), one of the three clinical awards targeting the coronavirus. This grant will support California Institutions participating in the Phase I/II clinical trial of human placental hematopoietic stem cell derived natural killer (NK) cells (CYNK-001) for the treatment of adults with COVID-19.The University of California Irvine is the first CA site to open for patient enrollment.

CIRM's COVID-19 Project supports promising discovery, preclinical and clinical trial stage projects that could quickly advance treatments or vaccines that utilize stem and/or progenitor cells. Celularity will use the CIRM grant to support the evaluation of the anti-viral activities of its cryopreserved investigational product, CYNK-001, in underserved and disproportionately affected populations with COVID-19, an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Celularity received clearance from the United States Food and Drug Administration to proceed with a Phase I/II study to evaluate the safety, tolerability, and efficacy of CYNK-001 in patients with COVID-19.

"Our investigational product CYNK-001 showed great promise in preclinical studies, and we are optimistic that it will prove effective against corona virus diseases, including COVID-19. As part of our rapidly-scalable placental-derived cellular medicine platform, CYNK-001 could play an important role in the public health response to outbreaks of COVID-19 or other coronaviruses," said Robert J. Hariri, MD, PhD, Founder, Chairman and CEO of Celularity. "We are very grateful to CIRM for supporting our effort to make novel cellular medicines available to medically underserved and disproportionately affected persons in California."

Xiaokui Zhang, PhD, Chief Scientific Officer and Principal Investigator under the CIRM grant says "CYNK-001 has a range of biological activities that not only recognize and destroy virus-infected cells, but also coordinate a robust immune response that may lead to an effective and durable defense against the viral infection."

The trial will evaluate the safety and the clinical efficacy of CYNK-001 in SARS-CoV-2 positive subjects as measured by clearance of the SARS-CoV-2 and improvement in clinical symptoms or improvement in radiological evaluation of disease related chest x-ray. The primary objective of the Phase I portion of the study is to evaluate the safety, tolerability, and efficacy of multiple CYNK-001 intravenous (IV) infusions in COVID-19 patients and will be administered to up to 14 patients in three doses over the course of seven days.

The Phase II portion of the study is a randomized, open-label, multi-site study measuring multiple doses of CYNK-001 against a control group experiencing a similar degree of infection with best supportive care, with two co-primary endpoints. The first co-primary endpoint is to determine the virologic efficacy of CYNK-001 in facilitating the clearance of SARS-CoV-2 from mucosal specimens and/or peripheral blood. The second co-primary endpoint is to assess the impact of treatment with CYNK-001 on clinical symptoms among patients with COVID-19 related lower respiratory tract infection.

Celularity has treated patients with severe COVID-19 and on ventilator support under compassionate use programs in U.S. CYNK-001 was well tolerated and may be associated with clinical benefit in selected cases.

About NK CellsNK cells are innate immune cells with an important role in early host response against various pathogens. Multiple NK cell receptors are involved in the recognition of infected cells. Studies in humans and mice have established that there is robust activation of NK cells during viral infection, regardless of the virus class, and that the depletion of NK cells aggravates viral pathogenesis.

About CYNK-001CYNK-001 is the only cryopreserved allogeneic, off-the-shelf NK cell therapy developed from placental hematopoietic stem cells. CYNK-001 is being investigated as a potential treatment option in adults with COVID-19, as well as for various hematologic cancers and solid tumors. NK cells are a unique class of immune cells, innately capable of targeting cancer cells and interacting with adaptive immunity. CYNK-001 cells derived from the placenta are currently being investigated as a treatment for acute myeloid leukemia (AML), multiple myeloma (MM), and glioblastoma multiforme (GBM). On 1 April, the U.S. Food and Drug Administration cleared the Company's Investigational New Drug (IND) application for the use of CYNK-001 in adults with COVID-19.

About COVID-19The virus causing COVID-19 is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is a novel coronavirus that has not been previously identified. COVID-19 has become a global pandemic, with over 4.2 million confirmed cases in the USA and over 650,000 deaths reported to date worldwide.

About CelularityCelularity, headquartered in Florham Park, N.J., is a next-generation Biotechnology company leading the next evolution in cellular medicine by delivering off-the-shelf allogeneic cellular therapies, at unparalleled scale, quality, and economics. Celularity's innovative approach to cell therapy harnesses the unique therapeutic potential locked within the cells of the post partum placenta. Through nature's immunotherapy engine the placenta Celularity is leading the next evolution of cellular medicine with placental-derived T cells, NK cells, and pluripotent stem cells to target unmet and underserved clinical needs in cancer, infectious and degenerative diseases. To learn more visit celularity.com

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Celularity announces the activation of first California Clinical Trial Site following CIRM Grant Award to Advance Treatments for COVID-19 - PRNewswire

Trending News on Targeted Oncology, Week of August 7, 2020 – Targeted Oncology

This week in oncology news, the FDA granted approval to belantamab mafodotin-blmf (GSK2857916; Blenrep), an immunoconjugate targeted B-cell maturation antigen, for the treatment of relapsed/refractory multiple myeloma and to tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid) as treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

A Biologics License Application was also submitted to the FDA for omburtamab, which is intended for the treatment of pediatric patients with central nervous system (CNS)/leptomeningeal metastasis from neuroblastoma. A Fast Track designation was also granted to BST-236 for the treatment of older adult patients with acute myeloid leukemia. An Orphan Drug designation was also granted to SM-88 for the treatment of patients with pancreatic cancer.

FDA Approves Belantamab Mafodotin for Relapsed or Refractory Multiple Myeloma

The FDA granted approval to belantamab mafodotin-blmf for the treatment of patients with relapsed or refractory multiple myeloma who previously received treatment with at least 4 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

FDA Approves Tafasitamab/Lenalidomide for R/R DLBCL

The FDA granted approval to the combination oftafasitamab-cxix plus lenalidomide for the treatment of adultpatients with relapsed or refractory DLBCLnot otherwise specified, including DLBCL arising from low-grade lymphoma, and patients who are not eligible for autologous stem cell transplant.

Cellular Therapies Provide Hopeful Outcomes as Treatment of Patients with Myeloma

In an interview with Targeted Oncology, C. Ola Landgren, MD, PhD, discussed the development of CAR T-cell therapy in the treatment landscape of multiple myeloma.

Salvage Blinatumomab Therapy Generates Durable Responses in Relapsed/Refractory DLBCL

Salvage therapy with blinatumomab (Blincyto) may induce durable complete responses and a survival benefit as treatment of patients with relapsed/refractory diffuse large B-cell lymphoma, according to findings from a pooled analysis of 3 clinical trials.

FDA Grants Orphan Drug Designation for SM-88 for Treatment of Pancreatic Cancer

The FDA has granted an Orphan Drug designation to SM-88 for the potential treatment of patients with pancreatic cancer.

Multiple Therapies Show Responses in Lung Cancer With ROS1 Fusions

Ben Levy, MD, discusses the mechanism of resistance such as the G2032R solvent front mutation in patients who received crizotinib (Xalkori) for lung cancer with ROS1 fusions and how to treat them.

Expert Perspective Tumor Board: Hepatocellular Carcinoma

In this series, Ghassan Abou-Alfa, MD, MBA, and a group of experts discuss the treatment landscape of patients with hepatocellular carcinoma in 4 separate case discussions.

Recommendations for Managing Patients With Lung Cancer During COVID-19 Era

In response to the COVID-19 pandemic, the European Society of Medical Oncology has published recommendations for the management of patients with lung cancer to maintain high-quality standards of treatment.

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Trending News on Targeted Oncology, Week of August 7, 2020 - Targeted Oncology

Find Out Why Bioreactor Market is thriving worldwide by top key players like mergency Response USA, Buddi US, LLC, Connect America – Owned

The Global Bioreactor Market Is Predicted to Reach to US$ 787.57 Mn Due to High Adoption of Bioreactor in Pharmaceutical Industries

The author of the report analyzed that the global Bioreactor market accounted for US$ 603.91 million in 2017. Bioreactor is an apparatus usually in cylindrical shape, which is used in the bioprocess technology. The vessel acts as biological catalyst which transform biowaste into biochemicals such as biofuels, biopharmaceuticals, cosmetics etc. The device is designed in such a way that it can easily process steps of segregation, purification, and handling of wastes in bioprocess technology.

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The increasing demand towards the production facility for multi drug is driving the single use bioreactor market.The product enables the line clearence and validation of impurities in the manufacturring process of the drugs. The flexibilty provided by the product such as cost reduction, minimum production time that too without compromising the quality of the drug is further giving rise to the use of single use bioreactor in various industries such as biotech, oil and engeries, food and bevrages, etc.

Bioreactor such as fluzied bed reactor and photobioreactor both lack theavailability of sterilized sensor and has lower volume capacity. These two parameters are vital to scale up the production process and enhancement of the product quality. Hence lacking of these parameters are leading towards poor temperature control, difficult to clean, erosion of internal components etc., which ultimately increases the capital cost and limiting the progress of the bioreactor market

A large number of biopharmaceutical companies are emerging in developing countries such as India, China, Japan, Southeast Asia, Brazil and many others. Bioreactos plays an important role in tissue engenieering, cell culture, drug manufacturing and hence, increase of these application in coming future will postively impact the growth of the market.

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Stem Cellto Remain the Dominant Application during the Forecast Period, 2018-2026

Bioreactors play an intensive role in tissue engineering. These reactors are applied for effective stem cell expansion as this cell is considered the source for various biomedical applications such as drug discovery, cell therapy and many others. Based on property of cell, bioreactor deliver suitable environment for stem cell expansion. Stirred tank bioreactor helps in uniform distribution of cells and nutrition, this equal distribution of nutrition provides adequate amount of oxygen inside the cells which help in growth of cells and maintain stem cells in normal metabolism. This further increases the clinical application of stem cells for therapeutic uses. Hence, this factor has increased the growth of bioreactor market.

North America to Remain the Dominant Region during the Forecast Period,2018-2026

The presence of a number of water management organization in this region has made it the largest market shareholder for bioreactor market. Bioreactor focuses on improving and helping the industrial water filtration process. North America has recorded 11% of worldwide installation of Bioreactor for commercial application. Due to more stringent regulations and water reuse strategies, it is expected that there will be a significant increase in bioreactor reactor market in the coming future.

Bioreactor Market isFragmented with the Presence of Global and Regional Players

Some of the key participants in global market are Sartorius AG (Germany), Thermo Fisher Scientific Inc. (U.S.), Merck KGaA (Germany) and GE Healthcare (U.S.), Danaher Corporation (U.S), Eppendorf AG (Germany), BBI Biotech (Germany), Biotron (Switzerland), Cellexus (UK), Fermentec (South Korea), Finesse (USA), Zenith (India). In November 2013, GE Healthcare Life Science launched a product i.e. ReadyToProcess WAVE 25 bioreactor system, this product is featured with integrated temperature sensors and load cells. These features are designed to make handling of cell cultures convenient during clinical process. It includes one filter heater for maintaining appropriate temperature range i.e.15 degrees to 32 degrees Celsius for cell culture expansion.

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BCLI: Phase 3 ALS Data Expected by the End of November 2020 – Zacks Small Cap Research

By David Bautz, PhD

NASDAQ:BCLI

READ THE FULL BCLI RESEARCH REPORT

Business Update

Topline Data from Phase 3 ALS Trial Before End of November 2020

BrainStorm Cell Therapeutics, Inc. (NASDAQ:BCLI) is currently conducting a Phase 3 clinical trial of NurOwn in patients with amyotrophic lateral sclerosis (ALS) (NCT03280056). A total of 200 patients were randomized 1:1 to receive NurOwn or placebo in the randomized, double blind, placebo controlled, multi-dose trial. Cells were extracted once from each patient prior to treatment, with all administrations of NurOwn derived from the same extraction of cells due to a cryopreservation process the company developed for long-term storage of mesenchymal stem cells (MSC). Just as with the companys prior studies, there was a 3-month run-in period prior to the first treatment with two additional NurOwn treatments occurring two and four months following the first treatment. The company is focusing the trial on faster-progressing ALS patients since those patients demonstrated superior outcomes in the Phase 2 trial of NurOwn. The primary outcome of the trial is the ALSFRS-R score responder analysis and we now anticipate topline results before the end of November 2020.

Update on Phase 2 Progressive Multiple Sclerosis Trial

BrainStorm is currently conducting a Phase 2 clinical trial of NurOwn in patients with progressive multiple sclerosis (MS) (NCT03799718). The trial is an open label, single arm study that is enrolling patients with progressive MS with Expanded Disability Status Scale (EDSS) scores of 3.0 6.5. The primary endpoint of the study is the safety and tolerability of three doses of NurOwn with secondary endpoints examining the timed 25-foot walking speed or 9-hole peg test (both validated MS clinical outcome assessments) along with paired cerebrospinal fluid (CSF) and blood biomarker analysis. The National Multiple Sclerosis Society awarded the company a $0.5 million grant to help fund the study.

The trial is now fully enrolled and we anticipate dosing to be completed for all patients by the end of 2020. While the company had previously considered performing an interim analysis, since topline data would be available soon after an interim analysis could be performed the company has decided against performing an interim analysis and will instead report topline data for all 20 patients when it becomes available.

NurOwn Derived Exosomes Show Promise in Preclinical ARDS Study

On July 23, 2020, BrainStorm announced the successful completion of the first milestone in developing an exosome-based platform for the treatment of severe acute respiratory distress syndrome (ARDS) caused by COVID-19. Exosomes are small vesicles (30-150 nm) that are secreted by all cell types. Exosomes from mesenchymal stem cells (MSCs), from which NurOwn is derived, can penetrate into deep tissues and deliver various bioactive molecules. In addition, they can be delivered both intravenously or intratracheally.

BrainStorm conducted a preclinical study of MSC-derived exosomes in a mouse model of lipopolysaccharide (LPS)-induced ARDS. Treatment with intratracheally administered exosomes resulted in a statistically significant improvement in various lung functions, including functional lung recovery and decreased lung damage, as judged by the lung disease severity score (P=0.03). In addition, they led to a reduction in a number of pro-inflammatory cytokines. Lastly, exosomes derived from MSC-NTF cells were superior to exosomes derived from nave MSC from the same donor.

We anticipate the results being submitted to a peer reviewed journal for publication and the company is currently deciding whether to initiate a clinical trial program in COVID-19 patients with ARDS.

Financial Update

On August 5, 2020, BrainStorm announced financial results for the second quarter of 2020. As anticipated, the company did not report any revenues during the second quarter of 2020. Net R&D expenses for the second quarter of 2020 were $5.7 million, compared to $3.6 million for the second quarter of 2019. The increase was primarily due to an increase in payroll and stock-based compensation and a decrease in support from the Israel Innovation Authority (IIA) and California Institute for Regenerative Medicine (CIRM) along with a decrease in costs related to the Phase 3 and Phase 2 clinical trials. Excluding participation from the IIA and CIRM, R&D expenses were $6.0 million in the second quarter of 2020, compared to $6.5 million in the second quarter of 2019. G&A expenses for the second quarter of 2020 were $1.7 million, compared to $1.3 million in the second quarter of 2019. The increase was primarily due to increased payroll and stock-based compensation.

The company exited the second quarter of 2020 with approximately $16.2 million in cash, cash equivalents, and short-term investments. Subsequent to the end of the quarter, the company raised gross proceeds of approximately $13.7 million from the $50 million ATM facility entered into in March 2020 through the sale of 945,082 shares at an average price of $14.48 per share. In addition, the company raised gross proceeds of approximately $6.3 million from the exercise of warrants. We estimate that the company currently has approximately $35 million in cash, cash equivalents, and short-term investments.

As of July 31, 2020, the company had approximately 31.5 million shares outstanding and, when factoring in warrants and stock options, a fully diluted share count of approximately 37.0 million.

Conclusion

The countdown is on to the topline data release for the Phase 3 ALS trial, with those results expected before the end of November 2020. Even with the great run the stock has had since its recent lows in March 2020, we continue to view the shares as undervalued as we currently forecast peak sales for NurOwn of >$1 billion in ALS, >$500 million in MS, and >$2 billion in Alzheimers disease. We recently made a slight change to our model, in which we decreased the discount rate from 17% to 13%, and combined with the recent financing activity has resulted in an increase to our valuation to $33 per share.

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New Report: Regenerative Medicine & Advanced Therapies Sector Thriving Despite COVID-19 – GlobeNewswire

Cell, Gene & Tissue-Based Therapy Developers Poised to Break Year-Over-Year Global Financing Records

WASHINGTON, D.C., Aug. 06, 2020 (GLOBE NEWSWIRE) -- via NEWMEDIAWIRE --The Alliance for Regenerative Medicine (ARM), the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies, today announces the publication of its H1 2020 Global Sector Report, Innovation in the Time of COVID-19. The report provides an in-depth look at trends and metrics in the gene, cell, and tissue-based therapeutic sector in the midst of the pandemic.

As the voice of the sector globally, ARM regularly publishes sector data reports to showcase clinical and scientific progress, as well as advancements and remaining challenges in the policy environment surrounding cell, gene and tissue-based therapies. The report also includes updated metrics on fundraising and clinical trials from more than 1,000 therapeutic developers worldwide.

Highlights from the H1 2020 Global Sector Report include:

Janet Lambert, CEO of ARM, commented:The regenerative medicine and advanced therapy sector has shown remarkable resilience in the face of many new challenges posed by COVID-19. Most importantly, were continuing to see patients benefit from the profound therapeutic effects of both approved products and those currently in clinical development. ARM will continue to work with our membership and with policymakers in the second half of 2020 to further advance these transformative technologies. We are committed to bringing these life-changing therapies to patients in need.

This report is the latest in ARMs series of global regenerative medicine sector reports, providing up-to-date metrics on financings and the clinical landscape, as well as expert commentary on key trends and progress in the field. The full report is availableonline here, with key sector metrics and infographicsavailable here. For more information, please visitwww.alliancerm.orgor contact Kaitlyn (Donaldson) Dupont atkdonaldson@alliancerm.org.

About the Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory and reimbursement initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-based therapies. Early products to market have demonstrated profound, durable and potentially curative benefits that are already helping thousands of patients worldwide, many of whom have no other viable treatment options. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing regenerative medicines and advanced therapies. In its 11-year history, ARM has become the voice of the sector, representing the interests of 360+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups. To learn more about ARM or to become a member, visithttp://www.alliancerm.org.

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Immatics Extends Cell Therapy Manufacturing Collaboration with UTHealth – marketscreener.com

Houston, Texas, Aug. 06, 2020 (GLOBE NEWSWIRE) --

Houston, Texas, August 6, 2020 Immatics N.V. (NASDAQ: IMTX; Immatics), a clinical-stage biopharmaceutical company active in the discovery and development of T cell redirecting cancer immunotherapies, today announced the extension of its cell therapy manufacturing collaboration with The University of Texas Health Science Center at Houston (UTHealth), in Houston, Texas. The continued collaboration grants Immatics access to UTHealths state-of-the-art cGMP manufacturing infrastructure at the Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory, enabling continued production and supply of Immatics specialized, cell-based product candidates for testing in multiple clinical trials. Maximum capacity of the facility is anticipated at 48 ACTengine T cell products per month. The new agreement will run until the end of 2024. Under the agreement, UTHealth will provide Immatics with exclusive access to three cGMP suites and support areas for the manufacturing of various Adoptive Cell Therapy (ACT) products. Therapeutic T cell production will be carried out by Immatics manufacturing personnel and will be supported by a UTHealth-Immatics joint quality team.

Steffen Walter, Ph.D., Chief Technology Officer at Immatics, commented: During the last five years, we have established a strong and productive partnership with UTHealth that has enabled the initiation of four ongoing clinical trials. As we remain focused on the development of our clinical pipeline, this extension of our collaboration with UTHealth will fulfill Immatics manufacturing needs for our early-stage ACT clinical programs for the next four years. Being able to rely on a partner with profound cell therapy expertise who is familiar with our technologies and can support cGMP cell therapy production is critical to ensuring the advancement of our clinical trials. We look forward to continuing this fruitful collaboration with the experts at UTHealth.

Fabio Triolo, D.d.R., M.Phil., Ph.D., The Clare A. Glassell Distinguished Chair and Director of the Cellular Therapy Core at UTHealth, added: Signing the extended contract with Immatics fits into our strategy at UTHealth of supporting the development of new treatments for patients in need. We therefore look forward to continuing our collaboration and further leveraging the potential of our manufacturing capabilities.

About Immatics ACT ProgramsACTengine is a personalized approach in which the patients own T cells are genetically modified to express a novel proprietary TCR cognate to one of Immatics proprietary cancer targets which are then reinfused back into the patient. Immatics latest proprietary ACTengine manufacturing processes are designed to generate cell product candidates within a short six day manufacturing window and to deliver highly proliferative T cells, with the capability to infiltrate the patients tumor and function in a challenging solid tumor microenvironment. The process is designed to rapidly produce younger, better-persisting T cells capable of serial killing tumor cells in vitro. Immatics is further advancing the ACT concept beyond individualized manufacturing with its product class ACTallo which is being developed to generate off-the-shelf cellular therapies.

More information on the clinical trials can be found at the following links: https://immatics.com/clinical-programs/ and https://clinicaltrials.gov/.

- ENDS -Notes to Editors

About ImmaticsImmatics combines the discovery of true targets for cancer immunotherapies with the development of the right T cell receptors with the goal of enabling a robust and specific T cell response against these targets. This deep know-how is the foundation for our pipeline of Adoptive Cell Therapies and TCR Bispecifics as well as our partnerships with global leaders in the pharmaceutical industry. We are committed to delivering the power of T cells and to unlocking new avenues for patients in their fight against cancer.

For regular updates about Immatics, visit http://www.immatics.com. You can also follow us on Twitter and LinkedIn.

About UTHealthEstablished in 1972 by The University of Texas System Board of Regents, The University of Texas Health Science Center at Houston (UTHealth) is Houstons Health University and Texas resource for health care education, innovation, scientific discovery and excellence in patient care. The most comprehensive academic health center in the UT System and the U.S. Gulf Coast region, UTHealth is home to Jane and Robert Cizik School of Nursing, John P. and Kathrine G. McGovern Medical School and schools of biomedical informatics, biomedical sciences, dentistry and public health. UTHealth includes The University of Texas Harris County Psychiatric Center, as well as the growing clinical practices UT Physicians, UT Dentists and UT Health Services. The universitys primary teaching hospitals are Memorial Hermann-Texas Medical Center, Childrens Memorial Hermann Hospital and Harris Health Lyndon B. Johnson Hospital. For more information, visit http://www.uth.edu.

About the Evelyn H. Griffin Stem Cell Therapeutics Research LaboratoryThe Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory, which is part of the Cellular Therapy Core at UTHealth, has been Immatics manufacturing partner since 2015. The site is a U.S. Food and Drug Administration (FDA)-registered and inspected cGMP facility that has received accreditation from the Foundation for Accreditation of Cellular Therapy (FACT) as well as certification from the Clinical Laboratory Improvement Amendment (CLIA) and the College of American Pathologists (CAP).

Forward-Looking StatementsCertain statements in this press release may be considered forward-looking statements. Forward-looking statements generally relate to future events or Immatics future financial or operating performance. For example, statements concerning the timing of product candidates and Immatics focus on partnerships to advance its strategy are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as may, should, expect, intend, will, estimate, anticipate, believe, predict, potential or continue, or the negatives of these terms or variations of them or similar terminology. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Immatics and its management, are inherently uncertain. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, but are not limited to, various factors beyond management's control including general economic conditions and other risks, uncertainties and factors set forth in filings with the Securities and Exchange Commission (SEC). Nothing in this presentation should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements, which speak only as of the date they are made. Immatics undertakes no duty to update these forward-looking statements.

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Impact of COVID-19 Outbreak on Canine Stem Cell Therapy Market Expected to Secure Notable Revenue Share During 2020-2026 – Research Newspaper

This Canine Stem Cell Therapy Market report includes worldwide topmost prime manufactures like (VETSTEM BIOPHARMA, Cell Therapy Sciences, Regeneus, Aratana Therapeutics, Medivet Biologics, Okyanos, Vetbiologics, VetMatrix, Magellan Stem Cells, ANIMAL CELL THERAPIES, Stemcellvet) in terms of company basic information, Product Category, Sales (Volume), Revenue (Million USD), Price, Gross Margin (%), Price, Cost, Growth Rate, Import, Export, Market Share and Technological Developments. Canine Stem Cell Therapy Market report provide the COVID19 Outbreak Impact analysis of key factors influencing the growth of the Canine Stem Cell Therapy market Size (Production, Value and Consumption). In the end, the Canine Stem Cell Therapy industry report introduced new project SWOT analysis, investment feasibility analysis, and investment return analysis.

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Scope of Canine Stem Cell Therapy Market:The non-invasive stem cell obtaining procedure, augmented possibility of accomplishing high quality cells, and lower price of therapy coupled with high success rate of positive outcomes have collectively made allogeneic stem cell therapy a preference for veterinary physicians. Moreover, allogeneic stem cell therapy is 100% safe, which further supports its demand on a global level. Pet owners are identified to prefer allogeneic stem cell therapy over autologous therapy, attributed to its relatively lower costs and comparative ease of the entire procedure.

A rapidly multiplying geriatric population; increasing prevalence of chronic ailments such as cancer and cardiac disease; growing awareness among patients; and heavy investments in clinical innovation are just some of the factors that are impacting the performance of the global healthcare industry.

On the basis on the end users/applications,this report focuses on the status and outlook for major applications/end users, shipments, revenue (Million USD), price, and market share and growth rate foreach application.

Veterinary Hospitals Veterinary Clinics Veterinary Research Institutes

On the basis of product type, this report displays the shipments, revenue (Million USD), price, and market share and growth rate of each type.

Allogeneic Stem Cells Autologous Stem cells

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The report offers in-depth assessment of the growth and other aspects of the Canine Stem Cell Therapy market in important countries (regions), including:

The Following Points Are Important In Performing A Competitive Assessment of Canine Stem Cell Therapy Market:

What will make the customer buy from this operation instead of the competition?

Comparison between the products/services to the competitors products/services of Canine Stem Cell Therapy market (Features, Service, Quality, Price, Distribution, And Brand).

List the companies involved in the production of these products/services.

Describe the Canine Stem Cell Therapy market concentration (Such As Large Number of Small Players or Small Number of Large Players).

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Impact of COVID-19 Outbreak on Canine Stem Cell Therapy Market Expected to Secure Notable Revenue Share During 2020-2026 - Research Newspaper

Calidi Biotherapeutics in San Diego receives FDA Approval for COVID-19 Treatment clinical trial – – KUSI

SAN DIEGO (KUSI) Calidi Biotherapeutics, Inc., a clinical-stage biotechnology company at the forefront of stem cell-based delivery of oncolytic viruses, announced that the Investigational New Drug (IND) application submitted by its partner, Personalized Stem Cells, Inc. (PSC), has received FDA approval for the treatment of COVID-19 and pneumonia patients using stem cell therapy.

Calidi has partnered with PSC for over two yearsmost recently contributing the stem cell lines used to manufacture treatment for the upcoming first trial, CoronaStem 1, which will be conducted among 20 hospitalized COVID-19 patients in California.

We are extremely pleased to continue our partnership with PSC, securing and providing stem cells from healthy donors in strict accordance with FDA guidelines, said Allan J. Camaisa, Chairman and CEO of Calidi Biotherapeutics. Weve seen the impressive capabilities of allogeneic mesenchymal stem cells firsthand through Calidis years of work, and strongly believe that they can help provide a therapeutic solution for the global pandemic, in addition to serving as vehicles for oncolytic virus delivery and potentiation upon direct injection into cancerous tumors. The combined effect of efficient cell-based delivery, direct cancer cell killing by the oncolytic viruses and induction of anti-tumor immunity is responsible for the potent anti-tumor effects of this approach not only at the injected tumor site, but also at distant metastatic tumor sites.

The CoronaStem 1 study will proceed in the coming weeks, managed and conducted by PSC, among a limited number of COVID-19 patients, as outlined in the IND submission. PSC plans to proceed onto a larger phase 2 clinical trial and potentially into FDA compassionate use programs to reach more patients pending the success of the initial trial.

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Calidi Biotherapeutics in San Diego receives FDA Approval for COVID-19 Treatment clinical trial - - KUSI

Edited Transcript of BLCM.OQ earnings conference call or presentation 6-Aug-20 9:00pm GMT – Yahoo Finance

Houston Aug 7, 2020 (Thomson StreetEvents) -- Edited Transcript of Bellicum Pharmaceuticals Inc earnings conference call or presentation Thursday, August 6, 2020 at 9:00:00pm GMT

Bellicum Pharmaceuticals, Inc. - CFO

* Richard A. Fair

Bellicum Pharmaceuticals, Inc. - President, CEO & Director

* Nicholas M. Abbott

Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology

Greetings, and welcome to the Bellicum Pharmaceuticals 2Q 2020 Financial Results and Corporate Update Conference Call. (Operator Instructions) As a reminder, this conference is being recorded. Thursday, August 6, 2020.

I would now like to turn the conference over to Stephen Jasper from Westwicke. Please go ahead.

Thank you. Good afternoon, everyone, and thank you for joining the call. With me today on the call is Rick Fair, Bellicum's President and Chief Executive Officer; and Atabak Mokari, Chief Financial Officer. Later, during the Q&A session, Aaron Foster, Head of Research, will also be available.

Earlier this afternoon, Bellicum released financial results for the second quarter and 6 months ended June 30, 2020. If you have not received this release or if you'd like to be added to the distribution list, you can do so on the Investor Relations page of the company's website.

As a reminder, today's conference call will include forward-looking statements made under the Private Securities Litigation Reform Act of 1995, including statements regarding Bellicum's research and development plans, clinical trials, plans regarding regulatory filings, review and approval of its product candidates, commercialization expectations and our financial outlook. These forward-looking statements involve a number of risks and uncertainties and reflect Bellicum's opinions only as of the date of this call. Bellicum undertakes no obligation to revise or publicly release the results of any revision to these forward-looking statements in light of new information or future events. Actual results may differ from those indicated by these forward-looking statements due to numerous factors, including those discussed in the Risk Factors section of Bellicum's Form 10-K for the year ended December 31, 2019, and 10-Q for the quarter ended June 30, 2020, filed with the Securities and Exchange Commission.

And now I will turn the call over to Rick Fair, Bellicum's President and CEO.

Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [3]

Thanks, Stephen. Good afternoon, everyone, and thanks for joining us. On our call today, I'll provide an update on our GoCAR pipeline, and Atabak will update you on our financial results. Before I talk about our individual programs, let me briefly remind you how GoCAR is differentiated from other cell therapy approaches. Our platform is unique in 2 distinct ways. First, we've engineered GoCAR to deliver more potent and durable efficacy relative to current generation cell therapies. We believe we can accomplish this primarily through our coactivation domain, MyD88, CD40 or MC. We believe MC signaling can boost effector cell proliferation and survival, enhance functional persistence by resisting exhaustion in the suppressive tumor microenvironment and stimulate the cancer patients' own immune system to attack tumors.

Second, we've engineered GoCAR for higher performance relative to current generation cell therapies, potentially offering superior control via our molecular switch technology. Other cell therapies behave unpredictably due to their autonomous activity, but GoCAR anti-tumor effects can be controlled by the scheduled intermittent administration of rimiducid. GoCAR activity can be dialed up or down by adjusting the interval between rimiducid doses or suspending further rimiducid administration. In our dual-switch product candidates, we can further improve controllability by incorporating our CaspaCIDe safety switch, which would -- can rapidly eliminate cells when triggered to manage acute toxicities if they occur.

We believe our GoCAR platform may address many of the shortcomings of current cell therapies. Our preclinical investigations have demonstrated some of these potential benefits, and we are now observing supportive evidence of these effects in the clinic. We are pursuing 2 strategic paths to establish clinical proof of concept: First, we are targeting solid tumors, where the effects of MC signaling may help overcome the challenges of the hostile tumor microenvironment, T cell exhaustion and heterogeneous antigen expression that have confounded previous CAR-T efforts. Our 2 solid tumor CAR-T -- GoCAR-T candidates, or BPX-601, targeting PSCA, and BPX-603 targeting HER2.

Our second strategy is the pursuit of an allogeneic off-the-shelf cell therapy. We believe that our GoCAR platform has the potential to drive proliferation and persistence of allogeneic immune cells and to stimulate a host immune response, both of which will be critical to delivering effective off-the-shelf therapies. We seek to demonstrate the value of our approach with our BCMA GoCAR-NK.

Let me now provide an update on each of these programs. BPX-601 targets prostate stem cell antigen or PSCA. The clinical data we have presented to date from an ongoing Phase I/II dose escalation trial in pancreatic cancer have shown encouraging safety, biologic activity, and biomarker data that supports the hypothesized benefits of the GoCAR platform in solid tumors. Specifically, we are particularly encouraged by observations of tumor infiltration, GoCAR-T mediated immunomodulation, persistence of cells for up to 9 months and changes in gene expression in the tumor microenvironment, consistent with a productive CAR-T cell immune response.

We are now enrolling Cohort 5C, our first-in-human evaluation of repeat rimiducid dosing. Our preclinical experience suggests that regular rimiducid dosing can reactivate and expand GoCAR-T cells in the presence of tumor antigen over time, without creating T cell exhaustion and thus, maximize the clinical efficacy potential. We plan to present interim results for this cohort at a medical meeting by the end of this year.

Like many others, we have experienced the COVID-19 related impact on screening and enrollment, which may impact the number of patients and duration of follow-up that we will present. In addition, primarily due to COVID-19 restrictions at our study sites, we have been unable to date to collect post-treatment biopsies in Cohort 5C, limiting to some degree what we can assess in these patients. We will continue to work with our investigators to overcome these COVID-19 obstacles to the extent possible, and are in the process of adding a few more sites to the study to increase prescreening activity.

Looking ahead, we have submitted a protocol amendment to the FDA with several modifications to the study. Upon FDA and IRB clearance of this amendment, we plan to expand eligibility to third-line pancreatic cancer patients, which we believe will enable more prescreening. Second, informed by the risk-benefit profile we've observed to date, we will extend dose escalation to 10 million cells per kilogram. Lastly, we will add a cohort of patients with hormone refractory, metastatic castration-resistant prostate cancer. Assuming prompt FDA clearance of this amendment, we expect to begin enrollment under this amended protocol later this year. Based on the data we've seen so far and the proposed study amendments, we remain optimistic about BPX-601, both as a product candidate and as proof-of-concept for our GoCAR platform.

Now let me update you on BPX-603. This program is Bellicum's first dual-switch product candidate, which has been designed to target solid tumors that express HER2. Academic CAR-T trials targeting HER2 have demonstrated clinical activity and reasonable safety. We believe that our dual switch technology in BPX-603 may be uniquely suited to improve upon these earlier efforts by driving greater efficacy through MC signaling and providing an extra layer of safety via our switch platform.

The FDA recently cleared our IND for BPX-603, and we are currently in study start-up to initiate a Phase I/II clinical trial later this year. The trial is a traditional 3 plus 3 dose escalation followed by Phase II expansions in multiple HER2-positive cancers. Dose escalation will begin at 100,000 cells per kilogram in a basket of HER2-positive solid tumors, and patients will be sequentially enrolled throughout dose escalation. Patients will receive standard Flu/Cy conditioning followed by BPX-603 cells. The first patient in each dose cohort will be followed without subsequent treatment, while the remaining patients in each cohort will receive weekly rimiducid to either dose-limiting toxicity or disease progression. We are excited to get this study underway, and we'll keep you posted on our progress.

Now let's move to our BCMA GoCAR-NK program. CAR-NK cells represent an intriguing next wave in the evolution of cell therapy, so we are excited about the potential for our first off-the-shelf GoCAR-NK candidate. NK cells may be particularly well suited for allogeneic cell therapy since they have innate cytotoxicity with low propensity for causing graft-versus-host disease.

We presented encouraging preclinical data from our NK discovery program at the 2019 SITC meeting and published a paper on this work, Blood Advances, this year in May. The data showed that our GoCAR platform synergizes with secreted IL-15 to enhance NK cell proliferation, survival and cytotoxic function. In addition, GoCAR-NK cells expressing our MC coactivation domain and IL-15 resulted in superior in vivo efficacy in multiple preclinical tumor models. Based on these initial investigations, we believe that GoCAR-NK cells have the potential to be a best-in-class off-the-shelf cell therapy. We selected BCMA as the target for our initial program since it is, well validated from autologous CAR-T studies, and we expect cell therapy to play a major role in multiple myeloma treatment.

The next step for the field is to deliver similar clinical benefit with an off-the-shelf therapy, which may provide faster and more certain time to treatment, greater scalability, convenience and a lower cost to manufacture. Based on our preclinical findings, we believe that GoCAR-NK may deliver more durable efficacy than other off-the-shelf cell therapy strategies. We will seek to demonstrate this in our development program. Our preclinical development is ongoing, and we expect to present additional data for this program by the end of 2020.

That concludes the summary of our programs. So let me now turn the call over to Atabak for a review of our financial results.

--------------------------------------------------------------------------------

Atabak Mokari, Bellicum Pharmaceuticals, Inc. - CFO [4]

--------------------------------------------------------------------------------

Thank you, Rick. R&D expenses were $11.8 million for the second quarter of 2020 compared to $20 million for the second quarter of 2019. The reduction in expenses in the second quarter of 2020 was primarily due to reduced expenses related to reduced RIVO-CEL-related activities, reduced expenses resulting from the April 2020 manufacturing facility sale and the reduction in force that was implemented during the second half of 2019. These reduced expenses were partially offset by increased expenses related to our GoCar-T and GoCAR-NK programs.

General and administrative expenses were $3.8 million for the second quarter of 2020 compared to $7.5 million during the comparable period in 2019. The lower expenses in the second quarter of 2020 was primarily due to the reduction in RIVO-CEL-related commercialization activities and the effect of the reduction in force that reduced employee-related charges.

Bellicum reported a net loss of $43.2 million for the second quarter of 2020 compared to a net loss of $26.9 million for the comparable period in 2019. The second quarter 2020 results included a noncash loss of $30.7 million related to the change in fair value of warrant liability and net gain on dispositions of $3.8 million due to the manufacturing facility sale.

Turning to our balance sheet. As of June 30, 2020, cash, cash equivalents and restricted cash totaled $68 million. In the second quarter, we had a cash loss from operations of approximately $14.2 million, which was a decrease from prior quarters given the steps we have taken to streamline the organization.

In April, Bellicum closed a transaction in which the MD Anderson Cancer Center acquired our manufacturing facility in Houston for $15 million. Concurrent with the transaction, Bellicum repaid $7 million of its Oxford Finance debt obligation.

Based on current operating plans, Bellicum expects cash utilization of $55 million to $65 million for the full year 2020 compared to cash loss from operations of approximately $30.5 million for the 6 months ended June 30, 2020. We believe that the current cash resources will be sufficient to meet operating requirements into the second half of 2021.

And now I'll hand the call back over to Rick.

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Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [5]

--------------------------------------------------------------------------------

Thanks, Atabak. Reviewing our accomplishments so far in 2020, I'm pleased by the advancement of our GoCAR pipeline across our 3 programs. I'm particularly enthusiastic as we anticipate an increasing number of potential data milestones. Over the next 24 months, for BPX-601, we expect to present 2 updates in pancreatic cancer and our first data in prostate cancer. For BPX-603, we expect steady start in our first patient from dose escalation. And for our GoCAR-NK program, we expect multiple preclinical presentations and IND submission.

I remain excited about Bellicum's future, the potential of our GoCAR pipeline and look forward to updating you on our future progress, including our first-in-human data with repeat rimiducid dosing and preclinical data on our GoCAR-NK program later this year.

I'll now open the call to questions. Operator?

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Questions and Answers

--------------------------------------------------------------------------------

Operator [1]

--------------------------------------------------------------------------------

(Operator Instructions) And our first question comes from the line of Jim Birchenough with Wells Fargo Securities.

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Nicholas M. Abbott, Wells Fargo Securities, LLC, Research Division - Director & Associate Analyst [2]

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It's Nick on for Jim. And keeping us on the toes there with a new way to register and address all of your question. So the first thing, Rick, on 601. So has there been any readthrough from emerging repeat dose rimiducid data that's sort of led to this, I think, what we'd interpret as a renewed interest in expanding the 601 program?

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Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [3]

--------------------------------------------------------------------------------

No, I think the expansion in the prostate, which is probably what you're referring to, Nick, is -- been a long-standing interest of ours. And I think we've now -- we're approaching the end of the dose escalation that we initiated in pancreatic cancer and now's the time to explore an expansion mode, a different tumor type. I think we all acknowledge that pancreatic cancer is a very challenging tumor. And we certainly don't want to miss a signal by not looking a little more broadly. So I think this is really just fulfillment of the previously articulated plan.

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Nicholas M. Abbott, Wells Fargo Securities, LLC, Research Division - Director & Associate Analyst [4]

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Okay. And then, in terms of the patients that you'll be enrolling with prostate cancer, do they have to fail the specific number of lines of treatment? And then, just from a perspective of this is a very bone-centric cancer, do you have preclinical data that supports that 601 is able to penetrate bone mets?

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Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [5]

--------------------------------------------------------------------------------

Yes. On your first question, eligibility inclusion criteria, patients have to have received an anti-androgen therapy and either received or are ineligible for a taxane. And then for the subsets of patients that qualify, either MSI-high for anti-PD-1 or BRCA mutant for PARP inhibitor have to have received those therapies as well. So it's a later line patient population.

As far as bone mets, I don't think we have any specific preclinical data for BPX-601, but we will certainly be looking at the translational data as we embark and treat the patients in the study.

--------------------------------------------------------------------------------

Nicholas M. Abbott, Wells Fargo Securities, LLC, Research Division - Director & Associate Analyst [6]

--------------------------------------------------------------------------------

And then just on 603, you gave us some outlines on -- of the trial design, so 3 plus 3, those patients. So is that the first patient at every dose level would not receive rimiducid?

--------------------------------------------------------------------------------

Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [7]

--------------------------------------------------------------------------------

Yes, that's correct. The -- so it's a traditional 3 plus 3 design with some modifications, and that's certainly one of them. So you would expect in each cohort and dose level in each of the study, the first patient would receive cells only, and the second 2 patients in the absence of a dose-limiting toxicity would receive cells plus weekly rimiducid.

--------------------------------------------------------------------------------

Nicholas M. Abbott, Wells Fargo Securities, LLC, Research Division - Director & Associate Analyst [8]

--------------------------------------------------------------------------------

And so presumably that first patient then will stay in the hospital, be intensively monitored. Do you have -- I mean, what -- can you discuss what the triggers are for administering the rapalog to activate the kill switch?

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Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [9]

--------------------------------------------------------------------------------

I think in summary, depending on the toxicity, it's essentially failure of standard of care. So these patients, as you say, will be admitted and will be monitored carefully. The on-target, off tumor effects that you'd be most interested in with this antigen, of course, are cardiopulmonary. So certainly, we'll be active monitoring. And if adverse events occur, they'll be treated with standard of care for whatever the adverse event. And then if standard of care fails, then they'll receive tensile and the small molecule activator of the safety switch in this construct.

--------------------------------------------------------------------------------

Operator [10]

--------------------------------------------------------------------------------

Our next question comes from the line of Kit Ma with Jefferies.

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Wai Kit Ma, Jefferies LLC, Research Division - Equity Associate [11]

--------------------------------------------------------------------------------

This is Kit. I'm on for Biren. I'm wondering what type of response can we expect with BPX-601 in the current trial. What will be the bar to move this forward into Phase II trial?

--------------------------------------------------------------------------------

Richard A. Fair, Bellicum Pharmaceuticals, Inc. - President, CEO & Director [12]

--------------------------------------------------------------------------------

Sure. Thanks, Kit. So it depends on the tumor type, of course. I think what we've said about pancreatic cancer is that you'd need to see something like a 15% response rate with a 6-month duration of response to be meaningful activity in the setting and be worth expansion in prostate cancer, probably a bit higher on the response rate, something more like a 30% to 35% response rate with similar durability to be a meaningful candidate to advance. So those are the thresholds that we're looking at.

--------------------------------------------------------------------------------

Operator [13]

--------------------------------------------------------------------------------

(Operator Instructions) Our next question comes from the line of Wangzhi Li with Landenburg.

--------------------------------------------------------------------------------

Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [14]

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Edited Transcript of BLCM.OQ earnings conference call or presentation 6-Aug-20 9:00pm GMT - Yahoo Finance

AlloVir raises $276M IPO to run broad cell therapy program – FierceBiotech

AlloVir has raised $276 million in an upsized IPO to fund development of allogeneic T-cell treatments for viral diseases. The money will equip AlloVir to embark on a broad clinical development program for a phase 3-ready cell therapy that targets five viruses.

Massachusetts-based AlloVir generates off-the-shelf virus-specific T cells in donors before stimulating their peripheral blood mononuclear cells to selectively activate and expand the therapeutic cells. By giving patients T cells that partially match their HLA subtype, AlloVir thinks it can kill virus infected cells without harming healthy cells or causing graft-versus-host disease.

Viralym-M is the most advanced manifestation of the approach. Baylor College of Medicine has taken the treatment for five common viruses through phase 2, setting AlloVir up to push the drug toward approval while generating clinical proof-of-concept data in other indications.

AlloVir plans to spend $98 million to take Viralym-M through phase 3 trials in immunocompromised patients post allogeneic hematopoietic stem cell transplant (HSCT) who have complications linked to hemorrhagic cystitis, cytomegalovirus or adenovirus. The phase 2 linked adenovirus Viralym-M to a 93% clinical response rate in HSCT patients with one or more treatment-refractory infections.

The size of the IPO means AlloVir has enough money to pursue other opportunities. In addition to the three phase 3 trials, AlloVir plans to start three phase 2 trials to test Viralym-M in the prevention of multi-virus infections in HSCT patients, and the treatment of BK and cytomegalovirus in kidney and solid organ transplant recipients, respectively.

AlloVir has set aside $83 million for the phase 2 program, leaving it with cash to spend on two other assets. A second cell therapy, ALVR106, is due to enter the clinic in autologous and allogeneic HSCT patients with respiratory viral diseases in the fourth quarter. AlloVir has earmarked $56 million for work on ALVR106.

A further $33 million will go toward a phase 1/2 trial of AlloVirs COVID-19 prospect. AlloVir joined the race to develop a COVID-19 treatment in March, teaming up with Baylor College of Medicine to create an off-the-shelf cell therapy against SARS-CoV-2 and other coronaviruses. The resulting drug, ALVR109, is made of CD4+ and CD8+ virus-specific T cells generated from healthy donors.

Baylor filed an IND for ALVR109 in June, only for FDA to hit it with a clinical hold earlier this month amid safety concerns related to the quality of ancillary reagents unique to ALVR109. Despite the setback, AlloVir still expects the trial to get underway this year and deliver top-line data in 2021.

Link:

AlloVir raises $276M IPO to run broad cell therapy program - FierceBiotech

NICE Amends Guidance on Haematopoietic Stem Cell Transplantation During the Pandemic – Medscape

The National Institute for Health and Care Excellence (NICE) has amended its recommendations on advice and testing for COVID-19 among patients undergoing haematopoietic stem cell transplantation and donors.

As of 29 July 2020,changeshave been made to the following sections:

Advice for patients to limit the number of family members who attend appointments (recommendation 1.3) and explaining measures to limit infection risk (new recommendation 1.4).

Advice for patients on minimising risk of respiratory infections before transplantation (recommendation 3.1).

Testing for respiratory viruses before transplantation (recommendation 3.2).

Additional investigations for patients who test positive for or are suspected of having COVID-19 (new recommendation 3.7).

Tests for donors and actions if the results are positive (new recommendation 4.5 and recommendation 4.6); these recommendations now apply to related donors, not just sibling donors (recommendation 4.1).

Risk assessment for donors who test positive (recommendation 4.8) and a reduction in the delay in providing blood products after a positive test (recommendation 4.10).

Advice for patients post-transplant (recommendation 5.2).

Assessing when staff who test positive or have symptoms can return to work (recommendation 6.2).

Routine screening for staff (new recommendation 6.3).

Prioritising treatment (table 1).

Risk assessments for ambulatory transplant pathways (new recommendation 8.3).

What to do when a centre is temproarily closed (recommendation 8.6).

Assessing risk in storing cells from a donor with COVID-19 (recommendation 8.9) and the viability of cryopreserved stem cells (new recommendation 8.10).

Using granulocyte-colony stimulating factor to minimise the use of chemotherapy priming.

NICE has also removed recommendations (originally numbered 3.3, 3.4 and 7.3) that advised deferring most autologous and allogeneic haematopoietic stem cell transplants, and deferring transplants if further treatment or immunosuppression would put them at more risk from COVID-19 in the community. This is to reflect changes in the risk of infection and the capacity in services.

This article originally appeared on Univadis, part of the Medscape Professional Network.

The rest is here:

NICE Amends Guidance on Haematopoietic Stem Cell Transplantation During the Pandemic - Medscape

Identification and Treatment of Tuberculosis in Pediatric Recipients o | IDR – Dove Medical Press

Xiaodong Wang1,2 ,* Uet Yu2 ,* Xiaonan Li,3 Chunjing Wang,2 Qian Zhang,2 Chunlan Yang,2 Xiaoling Zhang,2 Yu Zhang,2 Ying Wang,2 Yuejie Zheng,3 Jikui Deng,4 Weiguo Yang,5 Guosheng Liu,1 Guofang Deng,6 Sixi Liu,2 Feiqiu Wen1,2

1Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Peoples Republic of China; 2Department of Hematology and Oncology, Shenzhen Childrens Hospital, Shenzhen, Guangdong, Peoples Republic of China; 3Department of Respiratory Diseases, Shenzhen Childrens Hospital, Shenzhen, Guangdong, Peoples Republic of China; 4Department of Infectious Diseases, Shenzhen Childrens Hospital, Shenzhen, Guangdong, Peoples Republic of China; 5Pediatric Intensive Care Unit, Shenzhen Childrens Hospital, Shenzhen, Guangdong, Peoples Republic of China; 6Guangdong Key Laboratory for Emerging Infectious Diseases & Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third Peoples Hospital, Shenzhen, Guangdong, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Sixi Liu; Feiqiu Wen Email tiger647@126.com; fwen62@163.com

Background: Tuberculosis is a rare but life-threatening complication in patients who received hematopoietic stem cell transplantation. Early identification and intervention are essential to prevent severe complications.Case Presentation: We report two pediatric patients who developed tuberculosis after receiving hematopoietic stem cell transplantation for thalassemia major among 330 recipients between January 2012 and August 2019. Patient A presented with pulmonary tuberculosis and patient B presented with lymph node tuberculosis mimicking post-transplantation lymphoproliferative disorder associated with EpsteinBarr virus reactivation. Patient Bs condition was deteriorated, and shortly after the initiation of anti-tuberculosis therapy, the patient was found to have disseminated pulmonary tuberculosis. Patient B was also found to have tuberculous granulomas, an uncommon manifestation of tuberculosis causing severe airway obstruction. Both patients developed critical respiratory failure and required mechanical ventilation; however, they recovered with almost full resolution of pulmonary lesions after multiple treatment adjustments.Conclusion: Tuberculosis must be carefully evaluated in all pediatric patients that receive hematopoietic stem cell transplantation, regardless of the identification of other pathogens. Prophylactic tuberculosis therapy should be considered for high-risk pediatric hematopoietic stem cell transplantation recipients from tuberculosis-endemic regions.

Keywords: tuberculosis, hematopoietic stem cell transplantation, thalassemia, pediatric

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Identification and Treatment of Tuberculosis in Pediatric Recipients o | IDR - Dove Medical Press

Unproven ‘stem cell’ therapies for COVID-19 pose harm to public, says UB expert – UB Now: News and views for UB faculty and staff – University at…

Be wary of stem cell therapy as a preventative treatment for COVID-19, warns Laertis Ikonomou, a UB expert on stem cell and gene therapies.

While stem cell therapy, such as bone marrow transplantation, may be used to treat a limited number of diseases and conditions, there are currently no clinically tested or government-approved cell therapies available for the treatment or prevention of COVID-19, says Ikonomou, associate professor of oral biology in the School of Dental Medicine.

He urges the public to exercise caution as the nation experiences a rise in businesses offering direct-to-consumer, unproven and unsafe stem cell therapies that promise to prevent COVID-19 by strengthening the immune system or improving overall health.

What these patients are actually sold is false hope, he says. These businesses are continuously transforming and reinventing themselves, but the common thread is that they offer potentially dangerous treatments based on unproven science.

Ikonomou is also the chair of the International Society for Cell and Gene Therapy (ISCT) Presidential Task Force on the Use of Unproven and/or Unethical Cell and Gene Therapy.

Stem cell therapy involves the conversion of stem cells into specific types of cells, such as heart or blood cells. These cells are then transplanted into a patient to promote healing.

While there are companies that carefully develop cell-based treatments following established regulatory and ethical standards, there has also been an explosion of businesses since the mid-2000s that advertise directly to consumers and evade regulations to provide unsafe and ineffective treatments, he says.

These businesses operate in gray regulatory areas, frequently branding stem cell therapies as medical interventions rather than therapeutic drugs to avoid the need for U.S. Food and Drug Administration (FDA) approval, Ikonomou says, adding that according to published research, there are more than 1,000 of these unsafe businesses in the U.S.

They offer purported stem cell therapies for nearly every condition imaginable, from diabetes and autism to Alzheimers disease. There are also reports of people suffering physical harm including blindness and death from unsafe stem cell interventions, such as drawing and reinjecting patients with their own fat cells, he says.

Im not surprised that a lot of these businesses went into COVID treatments, says Ikonomou. They went where the money is and took advantage of peoples fears.

The treatments range in price from a few thousand to tens of thousands of dollars, and often patients are encouraged to receive the expensive infusions every few months. Many people go into severe debt to acquire these ineffective treatments, he says.

This year, the FDA has issued several letters to offending businesses, including those advertising cell therapies for COVID-19, says Ikonomou. The Federal Trade Commission has also cracked down on misleading advertising from stem cell therapy clinics, he says.

However, many of these clinics are small and difficult to track. Patient prudence is key to avoiding harmful interventions, he says.

Ikonomou shares a list of steps the public can take to ensure a stem cell therapy is safe, proven and ethical.

Ikonomou also urges patients to share any questions they have with their physicians, who often are the gatekeepers for medical treatment. His best advice to patients: If something sounds too good to be true, it probably isnt true.

For information on safe and ethical cell therapies, visit the ISCT website.

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Unproven 'stem cell' therapies for COVID-19 pose harm to public, says UB expert - UB Now: News and views for UB faculty and staff - University at...

Future Prospects of Animal Stem Cell Therapy Market 2020 | Trends, Growth Demand, Opportunities & Forecast To 2026 | Medivet Biologics LLC,…

Animal Stem Cell Therapy Market research is an intelligence report with meticulous efforts undertaken to study the right and valuable information. The data which has been looked upon is done considering both, the existing top players and the upcoming competitors. Business strategies of the key players and the new entering market industries are studied in detail. Well explained SWOT analysis, revenue share and contact information are shared in this report analysis.

Animal Stem Cell Therapy Market is growing at a High CAGR during the forecast period 2020-2026. The increasing interest of the individuals in this industry is that the major reason for the expansion of this market.

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Top Key Players Profiled in This Report:

Medivet Biologics LLC, VETSTEM BIOPHARMA, J-ARM, U.S. Stem Cell, Inc, VetCell Therapeutics, Celavet Inc., Magellan Stem Cells, Kintaro Cells Power, Animal Stem Care, Animal Cell Therapies, Cell Therapy Sciences, Animacel

The key questions answered in this report:

Various factors are responsible for the markets growth trajectory, which are studied at length in the report. In addition, the report lists down the restraints that are posing threat to the global Animal Stem Cell Therapy market. It also gauges the bargaining power of suppliers and buyers, threat from new entrants and product substitute, and the degree of competition prevailing in the market. The influence of the latest government guidelines is also analyzed in detail in the report. It studies the Animal Stem Cell Therapy markets trajectory between forecast periods.

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Table of Contents:

Global Animal Stem Cell Therapy Market Research Report

Chapter 1 Animal Stem Cell Therapy Market Overview

Chapter 2 Global Economic Impact on Industry

Chapter 3 Global Market Competition by Manufacturers

Chapter 4 Global Production, Revenue (Value) by Region

Chapter 5 Global Supply (Production), Consumption, Export, Import by Regions

Chapter 6 Global Production, Revenue (Value), Price Trend by Type

Chapter 7 Global Market Analysis by Application

Chapter 8 Manufacturing Cost Analysis

Chapter 9 Industrial Chain, Sourcing Strategy and Downstream Buyers

Chapter 10 Marketing Strategy Analysis, Distributors/Traders

Chapter 11 Market Effect Factors Analysis

Chapter 12 Global Animal Stem Cell Therapy Market Forecast

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Future Prospects of Animal Stem Cell Therapy Market 2020 | Trends, Growth Demand, Opportunities & Forecast To 2026 | Medivet Biologics LLC,...

Placental Stem Cell Collection and Storage Market 2020 Segmented by Major Market Players, Types, Applications and Countries Forecast to 2026 – Market…

The prime objective of GlobalPlacental Stem Cell Collection and Storage Market report is to help the user understand the market in terms of its definition, segmentation, market potential, influential trends, and the challenges that the market is facing with 10 major regions and 30 major countries. Deep researches and analysis were done during the preparation of the report. The readers will find this report very helpful in understanding the market in depth. The data and the information regarding the market are taken from reliable sources such as websites, annual reports of the companies, journals, and others and were checked and validated by the industry experts. The facts and data are represented in the report using diagrams, graphs, pie charts, and other pictorial representations. This enhances the visual representation and also helps in understanding the facts much better.

Impact of Covid-19 in Placental Stem Cell Collection and Storage Market: Report covers Impact of Coronavirus COVID-19: Since the COVID-19 virus outbreak in December 2019, the disease has spread to almost every country around the globe with the World Health Organization declaring it a public health emergency. The global impacts of the coronavirus disease 2019 (COVID-19) are already starting to be felt, and will significantly affect the Placental Stem Cell Collection and Storage market in 2020. The outbreak of COVID-19 has brought effects on many aspects, like flight cancellations; travel bans and quarantines; restaurants closed; all indoor/outdoor events restricted; over forty countries state of emergency declared; massive slowing of the supply chain; stock market volatility; falling business confidence, growing panic among the population, and uncertainty about future.

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By Market Players:AmericordPluristem TherapeuticsPSTICelularityCryobankReeLabsChina Cord Blood CorporationMesoblast LimitedAmericord RegistryLifebankUSAOcata TherapeuticsStemcyteCryoviva IndiaCaladrius BiosciencesH&B GroupViacordCryo-CellCBR Systems, Inc.Cells4LifeSmart Cells International Ltd.Cordlife

By TypePlacental Subtopotent Stem CellsPlacental Hematopoietic Stem CellsPlacental Mesenchymal Stem Cells (MSC)Placental Maternal Pluripotent Stem Cells

By ApplicationCell TherapyBeauty ProductsOther

Geographically, the detailed analysis of consumption, revenue, and market share and growth rate, historic and forecast of the following regions:

United States, Canada, Germany, UK, France, Italy, Spain, Russia, Netherlands, Turkey, Switzerland, Sweden, Poland, Belgium, China, Japan, South Korea, Australia, India, Taiwan, Indonesia, Thailand, Philippines, Malaysia, Brazil, Mexico, Argentina, Columbia, Chile, Saudi Arabia, UAE, Egypt, Nigeria, South Africa and Rest of the World

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Some Points from Table of Content

Covid-19 Impact on Global Placental Stem Cell Collection and Storage Industry Research Report 2020 Segmented by Major Market Players, Types, Applications and Countries Forecast to 2026

Chapter 1 Report OverviewChapter 2 Global Placental Stem Cell Collection and Storage Market Trends and Growth StrategyChapter 3 Global Placental Stem Cell Collection and Storage Market Players ProfilesChapter 4 Global Placental Stem Cell Collection and Storage Market Competition by Market PlayersChapter 5 Global Placental Stem Cell Collection and Storage Production by Regions (2015-2020)Chapter 6 Global Placental Stem Cell Collection and Storage Consumption by Region (2015-2020)Chapter 7 Global Placental Stem Cell Collection and Storage Production Forecast by Regions (2021-2026)Chapter 8 Global Placental Stem Cell Collection and Storage Consumption Forecast by Regions (2021-2026)Chapter 9 Global Placental Stem Cell Collection and Storage Sales by Type (2015-2026)Chapter 10 Global Placental Stem Cell Collection and Storage Consumption by Application (2015-2026)Chapter 11 Global Placental Stem Cell Collection and Storage Manufacturing Cost AnalysisChapter 12 Global Placental Stem Cell Collection and Storage Marketing Channel, Distributors, Customers and Supply ChainChapter 13 Analysts Viewpoints/ConclusionsChapter 14 Disclaimer

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Points Covered in The Report

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Placental Stem Cell Collection and Storage Market 2020 Segmented by Major Market Players, Types, Applications and Countries Forecast to 2026 - Market...