Clinical Responses With T Lymphocytes Targeting Malignancy-Associated Kappa Light Chains

BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the kappa light chain (kappa.CAR) and therefore recognizes kappa-restricted cells and spares the normal B cells expressing the nontargeted lambda light chain, thus potentially minimizing humoral immunity impairment.METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractoryr kappa(+) non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express kappa.CAR (kappa.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before kappa.CART infusion (0.2 x 10(8) to 2 x 10(8) kappa.CARTs/m(2)). No other lymphodepletion was used.RESULTS. kappa.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of kappa.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to kappa.CARTs were observed.CONCLUSION. kappa.CART infusion is feasible and safe and can lead to complete clinical responses.