Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas

Abstract

Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment of patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin lymphomas, in chronic lymphocytic leukemia, and in some cases of cutaneous and peripheral T-cell lymphomas. We found that CAR-37 T cells demonstrated antigen-specific activation, cytokine production, and cytotoxic activity in models of B- and T-cell lymphomas in vitro and in vivo, including patient-derived xenografts. Taken together, these results are the first showing that T cells expressing anti-CD37 CAR have substantial activity against 2 different lymphoid lineages, without evidence of significant T-cell fratricide. Furthermore, anti-CD37 CARs were readily combined with anti-CD19 CARs to generate dual-specific CAR T cells capable of recognizing CD19 and CD37 alone or in combination. Our findings indicate that CD37-CAR T cells represent a novel therapeutic agent for the treatment of patients with CD37-expressing lymphoid malignancies.

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

“…[26] T cells were cultured in media supplemented with rhIL-2 (20 IU mL −1 ) beginning on day 0 of culture and were maintained at a constant cell concentration (0.5 × 10 6 mL −1 ) by counting every 2-3 d. T cells were de-beaded at day 10 of culture and functional assays were performed at day 11, after resting overnight. Anti-BCMA CAR bears a CD8 hinge and transmembrane domain, 4-1BB costimulatory domain, and CD3 zeta signaling domain.…”

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…Various approaches have been used to overcome these challenges, including CRISPR-Cas9 genome editing to remove the antigen from the CAR T cells [45][46][47], Tet-OFF expression system to limit fratricide during ex vivo expansion [48], protein expression blocker (PEBL) to retain the antigen in the ER/Golgi to prevent cell surface expression [49,50], or using CAR-modified natural killer cells instead of T cells [47,[51][52][53][54]. Additionally, to date, four targets have been investigated as targets for CAR T cell therapy for the treatment of T cell malignancies with limited to no expression in the normal population of T cells, CD30, CD37, TRBC1, and CD1a [55][56][57][58]. Table 1 provides a summary of potential solutions to the three main challenges seen in adapting CAR technology for T cell malignancies-fratricide, T cell aplasia, and product contamination.…”

“…As a result, fratricide was observed only transiently, allowing the CD5-CAR T cells to expand. These cells had significant Genome editing of target antigen [45][46][47] Targeting antigens with limited expression on T cells (e.g., CD30, CD37, TRBC1, CD1a) [55][56][57][58] Tet-OFF expression system [48] Protein expression blockers (PEBLs) [49] Using NK cells or NK-92 cells [47,[51][52][53][54]60] T cell aplasia Targeting antigens with limited expression on T cells (e.g., CD30, CD37, TRBC1, CD1a) [55][56][57][58] mRNA electroporation…”

“…Since CD37 is not expressed in T cells, there is no evidence of fratricide occurring in anti-CD37 CAR T cells. However, in the presence of CD37-positive PTCL cell lines, CD37-CAR T cells exhibit increased activation and degranulation as well as specific cytolytic activity in vitro [56]. The restricted expression of CD37 makes it a safer target for CAR T cell therapy, given there would be no concern of T cell aplasia.…”

CAR‐T cells beyond CD19, UnCAR‐Ted territory

“…Some promising pre‐clinical and clinical targets in B‐cell malignancies beyond CD19 include CD22, CD20, ROR1, and CD37 and in multiple myeloma, kappa light chain, CD138, BCMA, SLAMF7, CD38, and integrin β 7 . CD20 is a B‐cell specific antigen that is present on a variety of lymphoid malignancies .…”