Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor–Redirected T Cells Against Multiple Myeloma

Abstract

Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat multiple myeloma-bearing mice as combinatorial therapy. CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. .

Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

“…However, TACI, like BCMA, exhibits heterogeneous expression in MM, and MM cells lacking expression of both antigens have been previously identified [14][15][16] . In contrast, CS1 (also known as SLAMF7 or CD319) is highly expressed on multiple types of MM and has been found on 90-97% of patient MM samples 17,18 , and an anti-CS1 CAR-T cell therapy 19 is currently being tested in the clinic (NCT03710421). We reason that simultaneous targeting of BCMA and CS1 would leverage the therapeutic efficacy of BCMA targeting while providing a safeguard against tumor escape due to BCMA loss.…”

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…89,93 Wang et al developed 2 second-generation CARs, 1 targeting B-cell maturation antigen (BCMA) and another targeting SLAMF7. 94 Although both CAR-Ts exhibited similar in vitro effector function, the anti-SLAMF7-CAR-T exhibited better antitumor activity than the anti-BCMA CAR-T in a mouse model. 94 Whether expression of SLAMF7 on NK cells and CD8 1 cells will be a limiting factor for widespread use will be evaluated in clinical trials.…”

“…Studies assessing combinations of CAR-Ts with other agents, including immunomodulatory drugs, are needed. 94 Initial results showed that addition of lenalidomide to anti-CS1 CAR T cells significantly improved CAR-T persistence and antimyeloma activity in preclinical experiments. 94 Conclusions CAR-Ts are a promising new approach for treating MM.…”

“…94 Initial results showed that addition of lenalidomide to anti-CS1 CAR T cells significantly improved CAR-T persistence and antimyeloma activity in preclinical experiments. 94 Conclusions CAR-Ts are a promising new approach for treating MM. Several patients have now obtained objective responses of MM after infusions of anti-BCMA CAR-T. 9,37,102,103 Cytokine-release toxicity has been severe in some patients receiving anti-BCMA CAR-T, but the toxicities have generally been reversible and short-lived.…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…Future directions to minimize tumor escape and increase effectiveness of CAR-T cell products include combinations [123] and modulation of the immunosuppressive tumor microenvironment through checkpoint inhibitors [124], combinations with immunomodulatory drugs [125], targeting the epigenome [126,127], incorporating novel costimulation [128] and dual targeting antigen [129]. In an attempt to improve safety and potency, advances in of CRISPR/Cas9 [130] and TALEN-mediated [131] genome-editing approaches for the large-scale manufacturing of 'off-the-shelf' CAR-T cells are outperforming conventionally transduction methods (NCT03399448).…”