Anti-CAIX BBζ CAR4/8 T Cells Have Superior Efficacy in a ccRCC

Wang Y, Buck A, Grimaud M, et al. Anti-CAIX BBζ CAR4/8 T Cells Exhibit Superior Efficacy in a ccRCC Mouse Model. Molecular Therapy: Oncolytics. 2022; 24 (doi: 10.1016/j.omto.2021.12.019).

Researchers have identified chimeric antigen receptor (CAR) T cells directed at carbonic anhydrase IX (CAIX) as having potentially robust therapeutic value in the setting of clear-cell renal cell carcinoma (ccRCC). CAIX is highly expressed in the disease, making it a strong therapeutic target for that patient population. However, recognizing that different types of solid tumors may be susceptible to distinct costimulatory domains, the team assessed anti-CAIX CAR-T cells with three different domains — BBζ, 28ζ, and 28BBζ — and different combinations of CD4/CD8. The greatest efficacy, persistence, and long-term immune surveillance was seen in second-generation BBζ CAR-T cells with a CD4/8 ratio of 2:1. Mice treated with a single dose of 3 million cells exhibited complete and long-term tumor remission. The effect is attributed to upregulated expression of major histocompatibility complex class II and cytotoxic-associated genes, downregulated exhaustion markers, and significantly diminished regulatory T cells. The investigators conclude that anti-CAIX BBζ CAR4/8 CAR-T cells "have the potential to be translated to clinic for treatment of ccRCC."

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