A novel KIR3DL2-directed CAR T-cell therapy for cutaneous and systemic T-cell lymphomas

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies and multiple myeloma, but its extension to T-cell lymphomas (TCLs) has been constrained by the paucity of antigens that can be safely targeted. While targeting pan-T antigens broadens the therapeutic reach across various TCLs, it carries a substantial risk of immunosuppression and infection. Here, we report killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR3DL2/CD158k) as a viable target for CAR T-cell therapy against a wide range of TCLs. Using single-cell RNA-seq data analysis and flow cytometric phenotyping, we observed that KIR3DL2 expression is restricted to a subset of mature NK cells and a minor fraction of CD8 T cells, with negligible expression in other healthy adult tissues. Among TCLs, KIR3DL2 expression was noted in various subtypes of cutaneous and systemic TCLs. Anti-KIR3DL2 CAR constructs (3DL2CARs) efficiently and selectively redirected T cells against antigen-positive cell lines but not isogenic KIR3DL2-negative counterparts, with antigen-specific signaling, cytotoxicity, proliferation, and cytokine production. Importantly, 3DL2CART cells produced sustained tumor regression and prolonged survival in two distinct cell line-derived xenograft models of cutaneous TCL and in one patient-derived xenograft model of hepatosplenic TCL. 3DL2CART cells exhibited minimal off-target activity against bystander immune cells and showed no appreciable fratricide. To mitigate the risk of tumor cell contamination in autologous CAR T-cell products, we established a two-tiered strategy that integrates immunomagnetic depletion of KIR3DL2-positive tumor cells with in vivo activation of a safety switch if inadvertently transduced malignant cells contribute to immune escape. Together, our results establish the preclinical efficacy and safety of 3DL2CART-cell therapy and support its clinical translation. This approach may offer a targeted alternative to pan-T-cell-directed CAR T-cell strategies for patients with relapsed/refractory cutaneous and systemic TCLs, addressing a critical unmet clinical need.