Abstract B26: Immunomodulatory activity of Isatuximab

Abstract

Abstract Isatuximab, previously known as SAR650984 is a naked chimeric IgG1 anti-CD38 monoclonal antibody. It is currently in clinical trials demonstrating single-agent activity in heavily pretreated relapsed/refractory multiple myeloma (RRMM). Isatuximab induces killing of CD38 positive tumor cells by triggering Fc dependent effector functions such as ADCC, ADCP and CDC, as well as Fc independent direct apoptotic effect. However, its effects in immune cells that express CD38 are emerging and are not yet well defined. The aim of this study was to investigate the effects of Isatuximab on immune effector cells, to better understand its anti-tumor mechanisms underlying the clinical benefit. Among immune sub-populations, Natural Killer (NK) cells and monocytes have the highest CD38 receptor density. Further, NK cells and monocytes play critical roles in immunity against cancer. We investigated Isatuximab's effect on these immune effector cells including their expansion, cytokine secretion and activation. Treatment (8 days at 1µg/ml) of 106 whole human peripheral blood mononuclear cells with Isatuximab induced expansion of NK and monocytes. In addition to enhance expansion, Isatuximab was able to induce the release of IFN-γ (~4000-7000 pg/ml) and TNF-α (~150-200 pg/ml) in NK cells in the absence of target cells. Incubation of Isatuximab (1µg/ml) for an hour also enhanced cytotoxic activity of human NK cells, both NK-92 cell line and isolated human NK cells, against CD38 negative K562 and JHH6 tumor cell lines. In the case of monocytes, Isatuximab activates phagocytosis by human monocytic cell line THP-1 and purified human monocytes. Furthermore, Isatuximab-activated NK cells can induce monocyte to M1 macrophage polarization through IFN-γ release in vitro. These findings collectively show evidence of Isatuximab being an immune-modulatory agent able to induce NK cell and monocyte activation. Further study is needed to determine whether Isatuximab's immunomodulatory activity could be utilized for the treatment of both CD38-positive and negative cancers by enhancing its anti-tumor function. Citation Format: Srimathi S. Srinivasan, Anlai Wang, Zhili Song, Francisco Adrián. Immunomodulatory activity of Isatuximab. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B26.