Chimeric Antibody Receptor-Encoded Epitopes Elicit Immune Responses in Patients Treated with Engineered T-Cells

Adoptive transfer of immune effector cells that are gene modified by retroviral transducion to express tumor-specific receptors constitute an attractive approach to treat cancer. In patients with metastatic renal cell carcinoma (RCC), we performed a study with autologous T-cells genetically retargeted with a chimeric antibody receptor (CAR) directed towards carbonic anhydrase IX (CAIX), an antigen highly expressed in RCC. In seven evaluable patients, we documented robust cellular and humoral anti-CAIX-CAR immune responses. In all cases, cellular immunity was directed against epitopes present in the complementarity-determining region (CDR) and framework region (FR) of the CAR-variable domains and occurred in the co-presence of an anti-idiotypic humoral response. The anti-idiotypic antibodies ware able to neutralize CAIX-CAR-mediated T-cell function. These immune responses preceded a decreased peripheral persistence of functional CAIX-CAR T-cells and therepy are likely to compromise their anti-tumor efficacy. These observations may constitute a critical concern for CAR-retargeted T-cell therapy and underscore the need to attenuate immunogenicity of this approach.