Lowering the antigen-binding domain affinity as a strategy of modifying CAR T-cell product

Introduction . Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high efficacy and safety in the clinical management of hematologic malignancies, such as B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. To achieve optimal therapeutic outcomes, CAR constructs with different architectures are being developed. Aim : to investigate whether modulation of the antigen-recognition domain (single-chain variable fragment, scFv) affinity reduction represents a promising strategy for optimizing CAR T-cell constructs. Main Findings . Lowering the affi nity of the antigen-recognition domain affects key characteristics of CAR T cells, including selectivity, expansion, persistence, and the exhaustion rate. Studies involving different target antigens have demonstrated that low-affinity CAR T-cells maintain or enhance antitumor activity while reducing on-target, off-tumor toxicity. Particular attention is given to the clinical application of obecabtagene autoleucel, the fi rst approved anti-CD19 CAR T-cell therapy incorporating a low-affinity scFv.