For all of the wondrous potential of immunotherapies, there have been some notable obstacles in the early goings. Engineering immune cells to attack cancerous tumors can lead to solid results shortly after administering a dose, but for many patients the effects wear off once rapidly mutating tumor cells acquire new defense mechanisms.
Cellectis (NASDAQ:CLLS) thinks it may have a partial solution. In mid-November, the gene editing company published the results from a proof of concept study for its "smart" immunotherapy approach. Is the technique the future of cellular medicine?
Image source: Getty Images.
Today, cellular oncology therapies genetically engineer immune cells to bolster their safety and efficacy as a cancer treatment. There are T cells, natural killer (NK) cells, tumor infiltrating lymphocytes (TILs), and others. They're often engineered with chimeric antigen receptors (CARs) or T cell receptors (TCRs), which allow them to home in on and suppress specific genes in cancer cells.
While current-generation CAR T cells or CAR NK cells are capable of mounting formidable attacks on tumors at first, treatment responses aren't durable for all patients. That's because cancer cells mutate to rely on different proliferation genes, or secrete new molecules into the tumor microenvironment that neutralize immune cells. Meanwhile, overstimulating the immune system can reduce the potency of immune cells and lead to devastating side effects, such as cytokine release syndrome.
That prompted Cellectis to design "smart" CAR T cells capable of adapting to changes in the tumor microenvironment. In a proof of concept study, the company utilized synthetic biology concepts to rewire genetic circuits in three different genes of the initial T cells.
One edit made the immunotherapy more potent, but in a controlled manner to reduce off-target toxicity. The other two edits imbued CAR T cells with the ability to secrete inflammatory proteins inside the tumor microenvironment in proportion to the concentration of cancer cells.
In other words, the smart CAR T cells only asked for help from the rest of the immune system when it was needed most, which increased the anti-tumor activity of treatment and made native immune cells less likely to become neutralized. That should reduce the likelihood of triggering cytokine release syndrome, the most common (and potentially fatal) side effect of cellular medicines, which is caused by high concentrations of immune cells.
The study was conducted in mice, which means the safety and efficacy observations can't be extrapolated into humans. But that wasn't the point. The proof of concept demonstrates that the basic idea of engineering tightly controlled genetic circuits into immunotherapies is feasible. It could even allow multiple genetic circuits of the same drug candidate to be tested against one another in parallel, hastening drug development and lowering costs. Is it the inevitable future of cellular medicine?
Image source: Getty Images.
Gene editing tools are required to engineer immune cells. In fact, immunotherapies are the lowest hanging fruit for gene editing technology platforms today. It's simply easier to engineer immune cells in the lab (ex vivo) than it is to engineer specific cell types in the complex environment of the human body (in vivo).
That explains why nearly every leading gene editing company has immunotherapy programs in its pipeline. Coincidentally, all of the leading drug candidates in the industry pipeline are off-the-shelf CAR T cells engineered to treat CD19 malignancies such as non-Hodgkin's lymphoma (NHL) and B-acute lymphoblastic leukemia (B-ALL), regardless of the gene editing approach used. The smart CAR T cells designed by Cellectis targeted CD22 malignancies, but the approach could be adapted to CD19 antigen.
Gene Editing Approach
Cellectis and Servier
Precision BioSciences (NASDAQ:DTIL)
ARCUS gene editing
CRISPR Therapeutics (NASDAQ:CRSP)
Sangamo Therapeutics (NASDAQ:SGMO) and Gilead Sciences (NASDAQ:GILD)
Zinc finger nuclease
Data source: Company websites.
Will these companies eventually turn to "smart" immunotherapies with regulated genetic circuits? It does seem inevitable, especially if the approach can reduce or eliminate cytokine release syndrome and enable more durable responses.
For example, Cellectis reported that all seven patients taking part in the phase 1 trial of UCART19 suffered from at least grade 1 cytokine release syndrome, which caused complications that led to the death of one patient. Five of the seven patients achieved molecular remission, but one relapsed (and remained alive) and one died. To be fair, all patients taking part in the trial had advanced, heavily pretreated B-ALL.
Precision BioSciences has encountered similar obstacles in an ongoing phase 1/2 trial of PBCAR0191. The company's lead drug candidate was administered to nine patients with NHL or B-ALL. Three cases of cytokine release syndrome were reported, but all were manageable. Seven responded to treatment, including two that achieved a complete response, but three eventually relapsed.
CRISPR Therapeutics recently began dosing patients with CTX110 in a phase 1/2 trial that will eventually enroll up to 95 individuals, but initial results won't be available until 2020. Sangamo Therapeutics and Kite Pharma, a subsidiary of Gilead Sciences, are plowing ahead with zinc fingers,but are still in preclinical development.
Investors seem pleased with most of these gene editing stocksright now. After all, despite the obstacles, current-generation cellular medicines are delivering impressive results in patient populations with relatively few options. But upcoming data readouts could easily differentiate the pack. That could increase the need to invest in augmented capabilities, such as smart immunotherapies.
There's plenty of untapped potential in cellular medicine. Today, companies are developing drug candidates with engineered CARs and TCRs designed to test hypotheses about the function of immunotherapies. As approaches find success, measured in safer and more durable responses, the next layer of complexity will be added in an effort to find even more successful therapies. And the cycle will continue.
Therefore, it seems inevitable that the field of cellular medicine will turn to smart immunotherapies with more complex genetic edits, much like the field quickly embraced the need for engineered immune cells and off-the-shelf manufacturing processes. That said, the immediate focus for Cellectis and its peers is building a stable foundation -- and those efforts have only just begun.
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