靶向人免疫球蛋白轻链的 CAR-T 细胞清除成熟 B 细胞恶性肿瘤并保留部分正常 B 细胞

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 - or -light chains. We initially constructed CAR-T targeting the -light-chain (CAR. ) and established a clinical study with it. After optimizing the CAR molecule, cells developed CAR-T targeting the -light chain (CAR. ) and we explored their antitumor activity. EXPERIMENTAL DESIGN: Using Ig + lymphoma cell lines and patient-derived Ig + CLL cells, we evaluated the in vitro tumor cytotoxicity and cytokine profiles of CAR. . We also assessed the in vivo efficacy of CAR. in xenograft Ig + lymphoma models including a patient-derived xenograft (PDX) of mantle cell lymphoma, and the effects of - or -light chain-specific CAR-T on normal B lymphocytes in a humanized murine model.

CAR. demonstrated antitumor effects against Ig + lymphoma cells and patient-derived CLL cells in vitro , and in vivo in xenograft and PDX Ig + lymphoma murine models. Antitumor activity of CAR. was superimposable to CAR.CD19. Furthermore, we demonstrated in the humanized murine model that - or -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. and CAR. -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. See related commentary by Jain and Locke, p. 5736 .