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

Abstract

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 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.

EXPERIMENTAL DESIGN:

Using 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.

RESULTS:

CAR.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.

CONCLUSIONS:

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.See related commentary by Jain and Locke, p. 5736.

• Authors: Raghuveer Ranganathan, Peishun Shou, Sarah Ahn, Chuang Sun, John West, Barbara Savoldo, Gianpietro Dotti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 21 Pg. 5951-5960 (11 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33858858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Immunoglobulin Light Chains
• Receptors, Chimeric Antigen

Topics

• Animals
• B-Lymphocytes (immunology)
• Humans
• Immunoglobulin Light Chains (immunology)
• Immunotherapy
• Lymphoma (immunology, therapy)
• Mice
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (immunology)