Novel CAR T-Cell Therapy Prioritizes Immune-Restoring Capability in RCC

Cellular therapy is not going to work on solid tumors unless the tumor microenvironment is changed, according to Wayne A. Marasco, MD, PhD. In a presentation he delivered at the 2025 Kidney Cancer Research Summit on a novel chimeric antigen receptor (CAR) T-cell therapy developed to target CAIX and CD70 in clear cell renal cell carcinoma (RCC), Marasco emphasized the importance of immune-restoring capabilities of cellular therapy.

In an interview with CancerNetwork® following the presentation, Marasco said that the CAR T cells his team developed secreted checkpoint blockade inhibitors at the tumor site. These inhibitors were able to reverse and block the tumor cells from commandeering the white blood cells, thus restoring local antitumor immunity while also reversing the local tumor immunosuppression.

The process of developing this CAR T-cell therapy that targets both the CAIX and CD70 molecules, which Marasco stated earlier in the interview took over a decade, emphasized the immune-restoring capabilities of the agent almost as much as it did the safety and efficacy.

Marasco is a professor in the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute, a professor of medicine at Harvard Medical School, and an associate physician in the Division of Infectious Diseases at Brigham and Women’s Hospital.

Transcript:

The immune-restoring capabilities, or the tumor microenvironment, are the third piece of this. In my opinion, cellular therapy is not going to work on solid tumors unless you change the tumor microenvironment. In other words, I mentioned earlier that the tumor cells commandeer the white blood cells. They send out signals and decoys to prevent the white blood cells from killing the tumor cells. We were able to engineer our CAR T cells so that they secreted, at the tumor site, molecules called checkpoint blockade inhibitors that reverse and block the commandeering of the tumor cells to impact the activity of the white blood cells. What we accomplish by doing that is to reverse the local tumor immunosuppression and restore local antitumor immunity. That does 2 things: It prevents the CAR T cells from becoming exhausted themselves once they get to that tumor, and equally important, they reverse the immunosuppression of those white blood cells that have already collected at the tumor. They know there's a tumor there, but they can't do anything about it because it has been inactivated. The therapy is designed to prevent CAR T-cell inactivation and to restore the antitumor immunity of the white blood cells that have gotten through the tumor to begin with.

Reference

Marasco WA. Redesigning CAR T cells for solid tumors: a new path toward cures of ccRCC. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.