3 years ago

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

Tea Gogishvili, Michael Hudecek, Julian Rydzek, Christian Brede, Sabrina Prommersberger, Martin Schreder, Sophia Danhof, Hermann Einsele
SLAMF7 is under intense investigation as a target for immunotherapy in multiple myeloma. Here, 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 prior treatment with proteasome-inhibitors and immunomodulatory agents (IMiDs). Consequently, SLAMF7-CAR T-cells conferred rapid cytolysis of previously untreated and R/R primary myeloma cells in vitro Further, 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 NK-cells, T-cells and B-cells. Following 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 recognition of normal lymophocytes 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 to utilize 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.

Publisher URL: http://doi.org/10.1182/blood-2017-04-778423

DOI: 10.1182/blood-2017-04-778423

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