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

Gogishvili T, Danhof S, Prommersberger S, Rydzek J, Schreder M, Brede C, Einsele H, Hudecek M (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Blood American Society of Hematology

Book Volume: 130

Pages Range: 2838-2847

Journal Issue: 26

DOI: 10.1182/blood-2017-04-778423

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 ofSLAMF7on 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 untreatedandR/R primarymyeloma 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, andBcells. After modification with theSLAMF7-CAR, bothCD81 andCD41 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+/high NK cells, CD4+ and CD8+ T cells, and B cells. Importantly, however, the fratricide conferred by SLAMF7-CAR T cells spares the SLAMF7-/low 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.

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE)

How to cite

APA:

Gogishvili, T., Danhof, S., Prommersberger, S., Rydzek, J., Schreder, M., Brede, C.,... Hudecek, M. (2017). SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood, 130(26), 2838-2847. https://doi.org/10.1182/blood-2017-04-778423

MLA:

Gogishvili, Tea, et al. "SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes." Blood 130.26 (2017): 2838-2847.

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