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

Purpose:

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.

Results:

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.

Conclusions:

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