CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B Cell Malignancies While Sparing a Subset of Normal B Cells.

Abstract

PURPOSE\nCD19-redirected chimeric antigen receptor (CAR.CD19) T cells promote clinical responses in patients with relapsed/refractory B cell non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL). However, patients showing sustained clinical responses after CAR.CD19-T treatment show increased infection risk due to compromised B-lymphocyte recovery. Mature B-cell-derived malignancies express monoclonal immunoglobulins bearing either κ- or λ-light-chains. We initially constructed CAR-T targeting the κ-light-chain (CAR.κ) and established a clinical study with it. We then modified the CAR molecule and then developed CAR-T targeting the λ-light chain (CAR.λ) and explored its antitumor activity.\n\n\nEXPERIMENTAL DESIGN\nUsing Igλ+ lymphoma cell lines and patient-derived Igλ+ CLL cells, we evaluated the in vitro tumor cytotoxicity and cytokine profiles of CAR.λ. We also assessed the in vivo efficacy of CAR.λ in xenograft Igλ+ lymphoma models including a patient derived xenograft (PDX) of mantle cell lymphoma, and the effects of λ- or κ-light-chain specific CAR-T on normal B-lymphocytes in a humanized murine model.\n\n\nRESULTS\nCAR.λ demonstrated antitumor effects against Igλ+ lymphoma cells and patient-derived CLL cells in vitro, and in vivo in xenograft and PDX Igλ+ lymphoma murine models. Antitumor activity of CAR.λ was superimposable to CAR.CD19. Furthermore, we demonstrated in the humanized murine model that λ- or κ-light-chain specific CAR-T cells only depleted the corresponding targeted light-chain expressing normal B cells, while sparing the reciprocal light-chain carrying B cells.\n\n\nCONCLUSIONS\nAdoptive transfer of CAR.λ and CAR.κ-T cells represents a useful and alternative modality to CAR.CD19-T cells in treating mature B-cell malignancies with minimal impact on humoral immunity.