American Association for Cancer Research
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10780432ccr202754-sup-247347_2_supp_6986228_qq001t.pptx (227.76 kB)

Figure S4 from CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells

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posted on 2023-03-31, 22:40 authored by Raghuveer Ranganathan, Peishun Shou, Sarah Ahn, Chuang Sun, John West, Barbara Savoldo, Gianpietro Dotti

Recurrent tumor cells in vivo

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Lymphoma Research Foundation Clinical Investigator Career Development

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ARTICLE 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 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. 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. 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

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