Fine-tuned anti-CAIX CAR and mitigation of OTOT toxicity
Wang Y, Buck A, Piel B, et al. Affinity Fine-Tuning Anti-CAIX CAR-T Cells Mitigate On-Target Off-Tumor Side Effects. Molecular Cancer. 2024; (doi: 10.1186/s12943-024-01952-w).
Researchers report that fine-tuning the affinity and avidity of chimeric antigen receptor (CAR) T cells specific to high carbonic anhydrase IX (CAIX) circumvents on-target off-tumor (OTOT) toxicity in clear cell renal cell carcinoma (ccRCC). OTOT side effects represent one of the greatest challenges holding back successful CAR application against solid tumors, which have few tumor-specific antigens to target. Instead, treatments rely on tumor-associated antigens (TAAs) that are expressed not only on cancer cells but on normal ones as well, leading to unfavorable outcomes. To enhance T-cell therapy for ccRCC, scientists focused on CAIX, a key therapeutic target for this patient population. They engineered a fine-tuned anti-CAIX CAR with G9, a low-affinity human single chain variable fragment. Under this construct, CAR T-cell activation occurs only in the presence of high levels of TAA, such as those expressed on tumor cells — and not when the TAA presents at physiologic levels on healthy cells. Subsequently, off-tumor killing on normal tissues with low levels of tumor antigen is mitigated.