CELL INTELLIGENCE · 肿瘤细胞治疗研究

Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective against B lineage malignancies. However, about half of patients either fail to achieve complete remission (in the case of lymphoma) or they relapse (in the case of acute lymphoblastic leukemia). CD22 represents an alternative highly B lineage-restricted target. Although CD22-targeted CAR-T cells are clinically active, targeting this antigen has proven difficult relative to CD19, attributable, in part, to lower expression levels. Commonly, patients relapse or progress with reduced CD22 expression compared to pre-treatment, contrasting with the loss of CD19 expression typically observed after CD19-CAR therapy. Prior work demonstrated that an antigen-independent "tonic" signaling CD22-CAR has enhanced clinical efficacy relative to other CD22-CARs tested. However, tonic signaling has been shown to be detrimental to long-term CAR-T cell function. Here, we demonstrate a balance between binding affinity and antigen-independent signaling (determined by length of the linker between fragment variable regions) in determining CAR function against CD22. We show that CAR function against both CD22 Lo and WT leukemia can be augmented by boosting binding affinity without shortening the linker to induce tonic signaling, establishing rational combinatorial modification of the antigen binding domain as an important approach for modulating the function of cellular therapeutics.