SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes

Abstract

SLAMF7 is under intense investigation as a target for immunotherapy in multiple myeloma. In this study, we redirected the specificity of T cells to SLAMF7 through expression of a chimeric antigen receptor (CAR) derived from the huLuc63 antibody (elotuzumab) and demonstrate that SLAMF7-CAR T cells prepared from patients and healthy donors confer potent antimyeloma reactivity. We confirmed uniform, high-level expression of SLAMF7 on malignant plasma cells in previously untreated and in relapsed/refractory (R/R) myeloma patients who had received previous treatment with proteasome inhibitors and immunomodulatory drugs. Consequently, SLAMF7-CAR T cells conferred rapid cytolysis of previously untreated and R/R primary myeloma cells in vitro. In addition, a single administration of SLAMF7-CAR T cells led to resolution of medullary and extramedullary myeloma manifestations in a murine xenograft model in vivo. SLAMF7 is expressed on a fraction of normal lymphocytes, including subsets of natural killer (NK) cells, T cells, and B cells. After modification with the SLAMF7-CAR, both CD8 and CD4 T cells rapidly acquired and maintained a SLAMF7 phenotype and could be readily expanded to therapeutically relevant cell doses. We analyzed the recognition of normal lymphocytes by SLAMF7-CAR T cells and show that they induce selective fratricide of SLAMF7 NK cells, CD4 and CD8 T cells, and B cells. Importantly, however, the fratricide conferred by SLAMF7-CAR T cells spares the SLAMF7 fraction in each cell subset and preserves functional lymphocytes, including virus-specific T cells. In aggregate, our data illustrate the potential use of SLAMF7-CAR T-cell therapy as an effective treatment against multiple myeloma and provide novel insights into the consequences of targeting SLAMF7 for the normal lymphocyte compartment.

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Anti-CD38 and anti-SLAMF7 CAR T cells showed anti-MM effects in preclinical models (47,48), but the expression of both target antigens on other normal tissues including hematopoietic lineages and immune effector cells may cause off-tumor toxic effects limiting their long-term clinical use. Being © 1996-2019 (57), and integrin β7 (58).…”

A review of chimeric antigen receptor T-cells in lymphoma

“…Clinical trials in multiple myeloma targeting B-cell maturation antigen (BCMA) have proven efficacy and safety of the use of CAR-T in this population [64]. Signaling lymphocyte-activating molecule F7 (SLAMF7), the monoclonal antibody target of elotuzumab, is another promising target in multiple myeloma given its lack of expression outside of hematologic cell line; however, CAR-T targeting this antigen has yet to be used in human clinical trials [65,66]. Many trials of CAR-T in multiple myeloma have shown consistent clinical response but optimization of dose and optimal target antigen still require refinement.…”

Non-viral therapeutic cell engineering with the Sleeping Beauty transposon system

“…Therefore, we consider SB transposition as a key enabling technology in order to make CAR-T cell therapy available on a global scale and in large patient cohorts. We have recently shown that CAR-T cells targeting the alternative myeloma antigen SLAMF7 are effective in pre-clinical models [68]. We are preparing a multi-center clinical trial with SLAMF7-specific CAR-T cells engineered with SB gene transfer (http://www.…”