Ranganathan R, Shou P, Ahn S, et al. CAR T Cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells. Clinical Cancer Research. 2021; (doi: 10.1158/1078-0432.CCR-20-2754).
When treating patients with relapsed/refractory B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia (CLL), adoptive transfer of chimeric antigen receptor (CAR) T cells targeting the λ-light-chain (CAR.λ) and the κ-light chain (CAR.κ) offer an alternative option to CD19-redirected CAR (CAR.CD19) T cells, with little effect on humoral immunity, a new study shows. Although CAR.CD19 T cells promote clinical responses in this patient population, there is an increased risk of infection among patients who demonstrate sustained clinical responses after treatment, the result of compromised B-lymphocyte recovery. However, mature B cell–derived malignancies express monoclonal immunoglobulins that include either λ- or κ-light chains. To evaluate the in vitro tumor cytotoxicity and cytokine profiles of CAR.λ, Igλ+ lymphoma cell lines and patient-derived Igλ+ CLL cells were used. The in vivo efficacy of CAR.λ in xenograft Igλ+ lymphoma models and the impact of λ- or κ-light chain–specific CAR T on normal B lymphocytes in a humanized murine model were also studied. CAR.λ exhibited antitumor effects against Igλ+ lymphoma cells and patient-derived CLL cells in vitro, and in vivo in xenograft and PDX Igλ+ lymphoma murine models. CAR.λ's antitumor effects showed no perceptible differences compared with CAR.CD19. In the humanized murine model, λ- or κ-light chain–specific CAR T cells only destroyed the corresponding targeted light chain–expressing normal B cells and spared the reciprocal light chain carrying B cells.