New research from a University of Minnesota team shows T cells can be engineered to migrate more effectively inside tumor microenvironments, raising hopes of reproducing the remarkable outcomes seen for certain hematological cancer patient subsets in broader populations and indications.
T cells have been key to two promising families of cancer immunotherapies, chimeric antigen receptor (CAR) T cells and immune checkpoint inhibitors. After two new U.S. Food and Drug Administration (FDA) approvals earlier this year for Bristol Myers Squibbs Breyanzi (lisocabtagene maraleucel) and Abecma (idecabtagene vicleucel), there are now five marketed CAR T cell therapies for a range of hematological cancers, including large B-cell and mantle cell lymphoma, acute lymphoblastic leukemia and multiple myeloma. These therapies are patient-derived T cells engineered to express a CAR that directs them to a specific tumor.
By contrast, immune checkpoint inhibitors function by targeting sets of natural immune system brakes, either on a tumor or directly on immune cells. The seven FDA-approved immune checkpoint inhibitors allow T cells to kill a growing list of hematological and solid tumors, and show impressive outcomes but in a fraction of patients.
Both approaches have been more effective in hematological cancers, and one obstacle in solid tumors is a literal barrier. T cells have to migrate through the complex, dense, and rigid tumor microenvironment, which can misdirect and slow down the immune cells.
The new paper, published in Nature Communications, shines a light on how T cells move within these physical features, informing new methods to rationally engineer the cells for more effective therapies.
T cell engineering has focused on cancer identification and targeting, said Paolo Provenzano, associate professor at the University of Minnesota Masonic Cancer Center and an author on the paper.
Were trying to add on a piece to that: they know what to kill, how do they get there? he said.
The researchers looked at pancreatic ductal adenocarcinoma (PDAC), a particularly fibrotic cancer known for limited cytotoxic T cell infiltration. Provenzano and colleagues had previously shown that antifibrotic therapies could improve immune cell infiltration in PDAC, but the group is now focused on rationally designing physical attributes of the T cells themselves.
Provenzanos team started by testing T cell migration on specialized artificial 2-D nanotextured platform that mimicked elements of the stromal extracellular matrix of tumors. T cells use lamellipodia and filopodia to sense biophysical cues and guide migration, and can switch between more flexible and stiffer phenotypes, to adapt to different conditions.
Theyre never all or one, theyre on this sliding scale, mediated by the muscle-like contractions of microtubules, Provenzano said.
The researchers found that while in a more amoebalike phenotype, cells had enhanced speed and motility, improving how quickly and effectively the cells could navigate the matrix. The researchers used the chemotherapeutic nocodazole, known to destabilize microtubules, to increase contractility and induce more amoebalike phenotypes, and another chemotherapeutic, paclitaxel, for the inverse. Cells with the nocodazole-induced amoebalike phenotypes could contract into smaller balls, and could shoot out protrusions faster, allowing for better motility than the paclitaxel-induced stiffer ones, and migrating between 50-100% faster in artificial 3-D matrices and mouse PDAC model tumor slices.
Thinking about personalized combination approaches to cancer treatment, this raised a red flag for Provenzano, as taxane agents are commonly used to treat solid tumors like breast and pancreatic cancer. The findings suggest certain chemotherapies might not be right if youre trying to elicit the bodys own immune response against these tumors, or mixing with a T cell therapy, he said.
The effect of chemotherapies on T cell microtubules is transient, so next the researchers explored a genetic engineering approach, using CRISPR technology to engineer T cells lacking GEF-H1, a gene they hypothesized mediates cell contractility. In a 3-D matrix, the knockout lines migrated 50% compared with controls.
Provenzano envisions different T cell engineering tweaks as part of the increasingly personalized approach to cancer treatment. Cells engineered to migrate faster have promise particularly in fibrotic tumor microenvironments, where T cells move about half as fast.
They get to sample less volume before they become exhausted, he said.
T cell exhaustion is a key limitation for CAR-T therapies and combining them with T cells that are physically optimized for faster migration could be synergistic in these patients.
If tumors are like unique obstacle courses for T cells, though, then different athletes or teams might be suited for different cancer types and patients.
Maybe we engineer five different T cells that navigate different obstacles, then mix them in cocktail and bring them back in. Thats what were thinking as our ultimate goal, he said.
Provenzanos lab is now using physics-based mathematical models to predict what the optimal cell would be.
We dont know the most physically optimized cell looks like yet, he said. But the paper represents just the first foray into the optimization process for just the first athlete. This will be what at least half my lab will be publishing on for the next decade.
There is active interest in the approach, but Provenzano said the work is not yet being commercialized. He hopes to find a partner with an ongoing T cell therapy clinical trial that could add an arm with his groups physically optimized cells, but trials are probably still years away.
Link:
Tumors Next Target for T Cell Therapies with U Minnesota Research - BioSpace
- Viewpoint: Anti-GMO arguments seem silly after 28 years of false narratives about health harms and and genetic ... - Genetic Literacy Project - March 29th, 2024 [March 29th, 2024]
- Viewpoint: Here's how genetically engineered fruits and vegetables will soon emerge as a grocery store 'selling point ... - Genetic Literacy Project - March 29th, 2024 [March 29th, 2024]
- CRISPR Investments: What We Heard at World Agri-Tech - Seed World - March 29th, 2024 [March 29th, 2024]
- When SpaceX's Starship is ready to settle Mars, will we be? (op-ed) - Space.com - September 17th, 2023 [September 17th, 2023]
- Genome-wide promoter responses to CRISPR perturbations of ... - Nature.com - September 17th, 2023 [September 17th, 2023]
- Expanding the toolbox for RNA editing | ASU News - ASU News Now - September 17th, 2023 [September 17th, 2023]
- Electrical Engineer Named MIT Technology Review Innovator Under ... - University of California San Diego - September 17th, 2023 [September 17th, 2023]
- Can we rely on our 'moral force-field' to stop cloning going too far? - The National - September 17th, 2023 [September 17th, 2023]
- Otsuka Collaborates with ShapeTX for Development of AAV Gene ... - Pharmaceutical Technology Magazine - September 17th, 2023 [September 17th, 2023]
- Cancer discovery earns U of A grad the Breakthrough Prize - University of Alberta - September 17th, 2023 [September 17th, 2023]
- The Brave New World of synthetic humans | Gne Taylor - IAI - September 17th, 2023 [September 17th, 2023]
- Targeting Tumors with Photosynthetic Bacteria - Optics & Photonics News - September 17th, 2023 [September 17th, 2023]
- Artificial Photosynthesis Breakthrough Researchers Produce ... - SciTechDaily - September 17th, 2023 [September 17th, 2023]
- BASF patent on watermelons upheld: European Patent Office rejects ... - Bio Eco Actual - September 17th, 2023 [September 17th, 2023]
- Space Industry Is Growing Faster Than Its Workforce, Analysts Say - Slashdot - September 17th, 2023 [September 17th, 2023]
- New 'Inverse Vaccine' Shows Potential to Treat MS and Other ... - Slashdot - September 17th, 2023 [September 17th, 2023]
- Gene therapy: Donor DNA may protect babies from certain disorders - Medical News Today - May 18th, 2023 [May 18th, 2023]
- Viewpoint: Grim consequences of Greenpeace's war on ... - Genetic Literacy Project - May 18th, 2023 [May 18th, 2023]
- Predicting Diabetic Kidney Disease with the Use of a Novel Algorithm - Genetic Engineering & Biotechnology News - May 18th, 2023 [May 18th, 2023]
- Quantum biology on horizon? How futuristic physics theory could ... - Study Finds - May 18th, 2023 [May 18th, 2023]
- Scientists can collect human DNA from water, air, and basically ... - Earth.com - May 18th, 2023 [May 18th, 2023]
- The First Crispr-Edited Salad Is Here - WIRED - May 18th, 2023 [May 18th, 2023]
- Gene editing technology used to produce disease-resistant calf - Earth.com - May 18th, 2023 [May 18th, 2023]
- Neanderthals passed down their tall noses to modern humans ... - Livescience.com - May 18th, 2023 [May 18th, 2023]
- Squid Camouflage Inspires Human Invisibility: Is it Possible? - DISCOVER Magazine - May 18th, 2023 [May 18th, 2023]
- Mice Model Technologies Market Poised for 7.4% CAGR Growth, Reaching USD 3.2 Bn by 2031 | Transparency Market Research - Yahoo Finance - May 18th, 2023 [May 18th, 2023]
- Google Cloud launches A.I.-powered tools to accelerate drug discovery, precision medicine - CNBC - May 18th, 2023 [May 18th, 2023]
- How Fauci, scientists with ties to Wuhan lab persuaded the ... - U.S. Right to Know - May 18th, 2023 [May 18th, 2023]
- The Daunting Task of Cutting Heavy Metals from Baby Food - Undark Magazine - May 18th, 2023 [May 18th, 2023]
- Ingestible Device Profiles and Peers into the Microbiome and ... - Genetic Engineering & Biotechnology News - May 18th, 2023 [May 18th, 2023]
- X-Men Officially Names the Best Powers Any Mutant Can Have - Screen Rant - May 18th, 2023 [May 18th, 2023]
- 10 Forgotten Marvel Comics Characters That Debuted In The '80s - Screen Rant - May 18th, 2023 [May 18th, 2023]
- 18 Human Genetic Engineering - Clemson University - April 19th, 2023 [April 19th, 2023]
- Pros and Cons of Genetic Engineering - Benefits and Risks - March 31st, 2023 [March 31st, 2023]
- What is Genetic Engineering? Types, Process & Applications - March 31st, 2023 [March 31st, 2023]
- How artificial skin is made and its uses, from treating burns to skin cancer - South China Morning Post - March 31st, 2023 [March 31st, 2023]
- Welcome to the UNC Department of Genetics | Department of Genetics - February 5th, 2023 [February 5th, 2023]
- Global Genetically Modified Crops Market Is Projected To Grow At A 6% Rate Through The Forecast Period - EIN News - February 5th, 2023 [February 5th, 2023]
- Science and History of GMOs and Other Food Modification Processes - February 2nd, 2023 [February 2nd, 2023]
- Genetics | History, Biology, Timeline, & Facts | Britannica - January 31st, 2023 [January 31st, 2023]
- Human genetics | Description, Chromosomes, & Inheritance - January 31st, 2023 [January 31st, 2023]
- Genetic testing - Mayo Clinic - January 31st, 2023 [January 31st, 2023]
- Genetic Disorders: What Are They, Types, Symptoms & Causes - January 31st, 2023 [January 31st, 2023]
- Colossal Biosciences Project to Revive the Prehistoric Woolly Mammoth Raises Staggering $60 Million Series A Funding - Nature World News - January 22nd, 2023 [January 22nd, 2023]
- 2023 is going to witness a surge in technology courses top courses that will remain in vogue - Times of India - January 22nd, 2023 [January 22nd, 2023]
- M.R.S. Rao birthday: All you need to know about the Padma Shri winning Indian scientist - Free Press Journal - January 22nd, 2023 [January 22nd, 2023]
- Russian cosmism - Wikipedia - January 8th, 2023 [January 8th, 2023]
- Postgenderism - Wikipedia - January 8th, 2023 [January 8th, 2023]
- LessWrong - Wikipedia - January 8th, 2023 [January 8th, 2023]
- Eliezer Yudkowsky - Wikipedia - January 8th, 2023 [January 8th, 2023]
- Genetic Engineering Principles of Biology - December 26th, 2022 [December 26th, 2022]
- Engineering the Perfect Baby | MIT Technology Review - December 26th, 2022 [December 26th, 2022]
- Genetic Engineering Science Projects - Science Buddies - December 21st, 2022 [December 21st, 2022]
- DSI adoption at COP15 can financially help protect biodiversity in India: Experts - The Tribune India - December 21st, 2022 [December 21st, 2022]
- Tel Aviv University researchers demonstrate success of potential one-time vaccine to treat HIV/AIDS - ETHealthWorld - December 21st, 2022 [December 21st, 2022]
- Should You Buy 22nd Century Group Inc (XXII) Stock After it Has Risen 14.29% in a Week? - InvestorsObserver - October 28th, 2022 [October 28th, 2022]
- Home :: National Institute for Biotechnology and Genetic Engineering - October 11th, 2022 [October 11th, 2022]
- A recently discovered law of physics could help predict genetic mutations - October 11th, 2022 [October 11th, 2022]
- Farmers, consumers will embrace GMOs if they understand them - The Standard - October 11th, 2022 [October 11th, 2022]
- Synthetic Biology Market is Expected to Report a CAGR of ~21% from 2021 to 2029: Industry Size, Growth & Forecast at Douglas Insights - Yahoo... - October 11th, 2022 [October 11th, 2022]
- After 45 years of science-based art, Esther Klein Gallery winds down - WHYY - October 11th, 2022 [October 11th, 2022]
- Behind this Nobel prize is a very human story: theres a bit of Neanderthal in all of us - The Guardian - October 11th, 2022 [October 11th, 2022]
- The key to tastier beer might be mutant yeastwith notes of banana - Popular Science - October 11th, 2022 [October 11th, 2022]
- Why You'll Probably Never See Cotton Candy Grape Wine - Tasting Table - October 11th, 2022 [October 11th, 2022]
- Earth materials in technology The National - The National - October 11th, 2022 [October 11th, 2022]
- CULINARY THRILL SEEKING Proceed with caution. It's hotter than blazes season. - Port Arthur News - The Port Arthur News - October 11th, 2022 [October 11th, 2022]
- Give legal rights to animals, trees and rivers, say experts - The Guardian - October 11th, 2022 [October 11th, 2022]
- How yeast DNA may help protect astronauts from cosmic radiation in space - EastMojo - October 11th, 2022 [October 11th, 2022]
- Life finds a way, but should it? The ethics of genetic engineering - The Trinitonian - October 8th, 2022 [October 8th, 2022]
- To modify or not to modify? Genetic Modification and Gene Editing - A divergence by the UK - Lexology - October 8th, 2022 [October 8th, 2022]
- Gene Therapy Hits Its Stride in the Clinic - Genetic Engineering & Biotechnology News - October 8th, 2022 [October 8th, 2022]
- GWAS, MWAS and mGWAS provide insights into precision agriculture based on genotype-dependent microbial effects in foxtail millet - Nature.com - October 8th, 2022 [October 8th, 2022]
- Making Sense of the Latest Apple-iPhone News - The Motley Fool - October 8th, 2022 [October 8th, 2022]
- Gene therapy brings hope to people with sickle cell, HIV - Monitor - October 8th, 2022 [October 8th, 2022]
- GMO: Everything you need to know about lifting ban - FarmKenya Initiative - The Standard - October 8th, 2022 [October 8th, 2022]
- Century Therapeutics to Present at the SITC 37th Annual Meeting - Yahoo Finance - October 8th, 2022 [October 8th, 2022]
- Cultured meat could help solve the climate crisis. Heres what it will take to move it from the lab to the dinner table - Fortune - October 8th, 2022 [October 8th, 2022]
- Poseida Therapeutics to Present Trial in Progress Poster for Phase 1 P-MUC1C-ALLO1 Study at the Society for Immunotherapy of Cancer Annual Meeting -... - October 8th, 2022 [October 8th, 2022]
- Explained: How scientists engineered mosquitoes that will cut the transmission of malaria - Firstpost - October 8th, 2022 [October 8th, 2022]
- Here Are the Biggest Health Industry News Items of 2022 So Far - DocWire News - October 8th, 2022 [October 8th, 2022]