Research spotlight: Preventing stalling to improve CAR-T cells’ efficacy against tumors

(Press-News.org) Marcela Maus, MD, PhD, director of the Cellular Immunotherapy Program and the Paula J. O'Keeffe Endowed Chair of the Mass General Cancer Center, is senior author and Stefanie Bailey, PhD, Hana Takei, and Giulia Escobar, PhD of the Krantz Family Center for Cancer Research at Massachusetts General Hospital are co-lead authors of a paper published in Science Translational Medicine, “IFN-g-resistant CD28 CAR-T cells demonstrate increased survival, efficacy, and durability in multiple murine tumor models.”

Q: How would you summarize your study for a lay audience?

Chimeric Antigen Receptor (CAR)-T cells are a promising cancer therapy that are made from the patient’s own T cells, which are reprogrammed to fight their cancer. One of the limitations of CAR-T cell therapy is the ability of these cells to survive long enough to target the entire tumor.

Once injected back into the patient, the CAR-T cells tend to rapidly expand when they become activated by the tumor cells, but eventually die off due to a natural process called activation-induced cell death.

We discovered a way to alter CAR-T cells so they can partially avoid activation-induced cell death, which allows them to live longer and better fight off the tumor.

Q: What question were you investigating?

This study was a follow-up to our previously published studies where we found that INFg was necessary for CAR-T cells to kill solid tumor cells, but not blood cancers.

IFNg is a cytokine released from CAR-T cells (and normal T cells) when they become activated that induces inflammation. If too much IFNg is released, it can cause toxicities in patients. Therefore, we created CAR-T cells that did not release IFNg.

In blood cancers, this led to decreased inflammation without affecting how well the CAR-T cells kill the tumor. However, in solid tumors, CAR-T cells that did not release IFNg did not kill tumor cells as well.

In both cases, CAR-T cells not releasing IFNg tended to expand more and live longer – two characteristics that would be advantageous for CAR-T cell efficacy.

In this study, we created CAR-T cells that still release IFNg (to maintain their ability to kill solid tumors) but continue to expand more and live longer, as if they are not releasing IFNg.

 

Q: What methods or approach did you use?

We used CRISPR/Cas9 to knock out expression of the IFNg receptor (IFNgR) in the CAR-T cells. Without this receptor, IFNg has no way of signaling to the CAR-T cell.

We used T cells from healthy donors to make the IFNgR-knockout CAR-T cells and examined their function in response to cancer cell lines in a dish.

We also injected these CAR-T cells into mice with tumors to demonstrate their improved persistence and function in a preclinical model.

Q: What did you find?

We found that knocking out IFNgR in CAR-T cells boosted their expansion, persistence and anti-tumor activity in both dishes and mouse models, enhancing their effectiveness and durability.

CAR-T cells that were unable to respond to IFNg signaling underwent less cell death following activation – i.e. deleting the IFNgR preventing the CAR-T cells from stalling.

Overall, this led to increasing CAR-T cell efficacy and expansion in multiple models of solid tumors.

Q: What are the implications?

These findings suggest that knocking out IFNgR from CAR-T cells would be improve their efficacy for targeting any tumor type by prolonging their survival and allowing them to kill more cancer cells.

Q: What are the next steps?

We hope to initiate a clinical trial of these CAR-T cells in patients with solid tumors, either in collaboration with a company or as a spin-out endeavor.

Authorship: In addition to Maus, Bailey, Takei and Escobar, other authors from Mass General Brigham include Michael C. Kann, Amanda A. Bouffard, Tamina Kienka, Valentina M. Supper, Alexander Armstrong, Diego Salas-Benito, Merle K. Phillips, Filippo Birocchi, Sonika Vatsa, Harrison Silva, Irene Scarfò, Marc Wehrli, Korneel Grauwet, Eli P. Darnell, Charlotte E. Graham, Mark B. Leick, Felix Korell and Trisha R. Berger.

Paper cited: Bailey S R et al., “IFN-g-resistant CD28 CAR-T cells demonstrate increased survival, efficacy, and durability in multiple murine tumor models” Science Translational Medicine, DOI: 10.1126/scitranslmed.adp8166

 

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