Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Autologous T cells genetically modified to express a chimeric antibody receptor(CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients withCAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated inthree cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 ×10⁹ CAR T cells. CTC grade 2–4 liver enzyme disturbancesoccurred at the lowest CAR T cell doses, necessitating cessation of treatment infour out of eight patients in cohorts 1 and 2. Examination of liver biopsiesrevealed CAIX expression on bile duct epithelium with infiltration of T cells,including CAR T cells. Subsequently four patients were pre-treated with CAIXmonoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed noliver toxicities and indications for enhanced peripheral T cell persistence. Noclinical responses were recorded. This report shows that CAIX-targeting CAR Tcells exerted antigen-specific effects in vivo and induced livertoxicity at the lowest dose of 0.2 × 10⁹ T cells applied,illustrating the potency of receptor-modified T cells. We provide in-patientproof that the observed “on-target” toxicity is antigen-directed andcan be prevented by blocking antigenic sites in off-tumor organs and allowinghigher T cell doses.