Chimeric antigen receptor (CAR) T cell therapy has come to the forefront of human cancer immunotherapy research. CD19-targeting CAR T cells (CARTs) have shown promising clinical efficacy against B cell malignancies, but prolonged CART persistence is required and can result in severe B cell aplasia/hypogammaglobulinemia. Ramos and colleagues of Baylor College of Medicine report the clinical safety and efficacy of κ-light chain-targeting CARTs (κ.CARTs), which limit B cell depletion by selectively destroying κ-expressing B cells but not λ-expressing B cells. In a Phase 1 clinical trial, 16 patients with κ+, relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) were treated with one or more infusions of κ.CARTs. κ.CARTs reached maximum expansion 1-2 weeks after infusion and persisted for at least 6 weeks. Importantly, κ.CART infusions were well-tolerated, did not contribute to any of the reported adverse events, and in MM patients, produced a 50% reduction in circulating B cells with preferential depletion of κ+ cells. Four out of the nine NHL/CLL patients demonstrated clinical responses to κ.CART therapy, ranging from complete response to stable disease. Four out of the seven MM patients responded to therapy with stable disease, minimal residual disease, or improvement of disease symptoms. These patients received limited lymphodepleting chemotherapy and/or had CD19.CART-resistant disease, indicating the feasibility and potential advantages of κ.CART therapy. Taken together, the results of this study demonstrate that κ.CART-based treatment for B cell malignancies is clinically promising and has the potential to limit major, inherent adverse effects. The accompanying image shows PET (upper panels)/CT (lower panels) images of a neck tumor mass in an NHL patient with complete response to κ.CART therapy. Note that the initial tumor (left panels) decreased in size 6 weeks after the first infusion (center panels) and was undetectable 6 weeks after the second infusion (right panels).
Carlos A. Ramos, Barbara Savoldo, Vicky Torrano, Brandon Ballard, Huimin Zhang, Olga Dakhova, Enli Liu, George Carrum, Rammurti T. Kamble, Adrian P. Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Gianpietro Dotti