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

Abstract

CD19-redirected chimeric antigen receptor (CAR.CD19) T cells promote clinical responses in patients with relapsed/refractory B-cell non-Hodgkin lymphomas 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. After optimizing the CAR molecule, cells developed CAR-T targeting the λ-light chain (CAR.λ) and we explored their antitumor activity. Using Igλ⁺ lymphoma cell lines and patient-derived Igλ⁺ CLL cells, we evaluated the <i>in vitro</i> tumor cytotoxicity and cytokine profiles of CAR.λ. We also assessed the <i>in vivo</i> 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. CAR.λ demonstrated antitumor effects against Igλ⁺ lymphoma cells and patient-derived CLL cells <i>in vitro</i>, and <i>in vivo</i> 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. Adoptive 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.<i>See related commentary by Jain and Locke, p. 5736</i>.