Elotuzumab, an hSLAMF7 antibody used for the treatment of multiple myeloma (MM), promoted human NK cell activation in vitro, and reduced tumor growth in mice by increasing NK cell activation and ADCC activity, as well as CD8+ T cell activation and granzyme B release. Coadministration of elotuzumab and anti-PD-1 enhanced tumor regression and survival in mice, generating immunological memory and providing a rationale for clinically investigating simultaneously targeting both innate and adaptive immune cells in patients with MM.

Elotuzumab, a humanized monoclonal antibody that binds human signaling lymphocytic activation molecule F7 (hSLAMF7) on myeloma cells, was developed to treat patients with multiple myeloma (MM). Elotuzumab has a dual mechanism of action that includes the direct activation of natural killer (NK) cells and the induction of NK cell-mediated antibody-dependent cellular cytotoxicity. This study aimed to characterize the effects of elotuzumab on NK cells in vitro and in patients with MM and to determine whether elotuzumab antitumor activity was improved by programmed death receptor-1 (PD-1) blockade. Elotuzumab promoted NK cell activation when added to a coculture of human NK cells and SLAMF7-expressing myeloma cells. An increased frequency of activated NK cells was observed in bone marrow aspirates from elotuzumab-treated patients. In mouse tumor models expressing hSLAMF7, maximal antitumor efficacy of a murine immunoglobulin G2a version of elotuzumab (elotuzumab-g2a) required both Fcgamma receptor-expressing NK cells and CD8(+) T cells and was significantly enhanced by coadministration of anti-PD-1 antibody. In these mouse models, elotuzumab-g2a and anti-PD-1 combination treatment promoted tumor-infiltrating NK and CD8(+) T-cell activation, as well as increased intratumoral cytokine and chemokine release. These observations support the rationale for clinical investigation of elotuzumab/anti-PD-1 combination therapy in patients with MM.

Author Info: (1) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (2) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (3) Biologics Discovery California, Bristol-Myers Squibb, Redwood

Author Info: (1) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (2) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (3) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (4) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (5) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (6) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (7) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (8) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (9) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (10) Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA. (11) Medical Oncology, Bristol-Myers Squibb, Princeton, NJ; and. (12) Discovery Research, Bristol-Myers Squibb, Lawrenceville, NJ.

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