A Decade of Research Led to Reduced Toxicity With Novel CAR T-Cell Therapy in RCC

In the past, CAIX was a clear cell renal cell carcinoma (RCC) target associated with extreme liver and biliary toxicity; however, Wayne A. Marasco, MD, PhD, believes that, after a decade of research, they’ve found a way to reduce the toxicity.

Following a presentation at the 2025 Kidney Cancer Research Summit on a novel CAR T-cell therapy that targets both the CAIX and CD70 targets in patients with clear cell RCC, Cancer Network® spoke with Marasco about these findings.1

According to Marasco, a previous study demonstrated “extreme toxicity” when utilizing the CAIX molecule as a target because the CAR T-cells would attack the healthy cells located in the cholangiocytes, as well as the tumor-associated cells. Now, after a decade of research, Marasco claims they’ve found a target moiety so that it only recognizes the high-density CAIX that is associated with tumors.

He also mentioned that CD70, the other molecule being targeted, was less of a hurdle because they were able to locate those types of antibodies through their screening process.

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 biggest hurdle was safety because, as I had mentioned, very early in the era of cellular therapy and CAR T-cell therapy, there was a clinical trial that took place at Memorial Sloan Kettering by an investigator named [Cor H.J. Lamers]. At the time, CAR T cells were in the infancy stage, and their designs have changed considerably to make them work now; before, they didn't work as well. That [study] was an example of an early generation CAR that was directed to CAIX, or [carbonic anhydrase IX], that didn’t have the features of a second generation, which is now what’s in the clinic. What they experienced there was extreme toxicity because the CAIX molecule is expressed on their cholangiocytes—the surface in the biliary duct—and they had liver and biliary toxicity.

We spent a decade or more finding the targeting moiety so that it would only recognize high-density CAIX that is typically found on tumor cells, but not low-density CAIX that is expressed in healthy cholangiocytes and cells in the bile duct. By doing so, and then testing the various iterations, we were able to demonstrate that we could prevent that toxicity from occurring in otherwise healthy tissues, so that took care of the major safety issue. The other molecule, CD70, was not much of a problem because we were able to get those types of antibodies out of our screens. What we’re looking for is called “high avidity”, so they only recognize high-density targets on tumor cells. Those targets are also expressed in healthy cells, not low-density [cells]—they selectively recognize tumor-associated [cells] but not those same antigens that are in healthy tissues. That’s how we solve the safety issue.

Reference

1. 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.
2. Lamers CH, Klaver Y, Gratama JW, Sleijfer S, Debets R. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells-a completed study overview. Biochem Soc Trans. 2016;44(3):951-959. doi:10.1042/BST20160037