Abstract 4617: Daratumumab combined with CD38(-) natural killer cells armed with a CS1 chimeric antigen receptor for the treatment of relapsed multiple myeloma
Authors: Wang Yufeng , Zhang Yibo , Bnson Don , Caligiuri Michael , Yu Jianhua 
Published: July 2017

Abstract
Multiple myeloma (MM) is the second most frequent hematological cancer in developed countries. The recent development of monoclonal antibodies, including Daratumumab (Dara) approved by the FDA, is changing the treatment algorithm of MM. However, MM still relapses and remains incurable. Recently, chimeric antigen receptor (CAR) T cell immunotherapy has been successful in the clinic for the treatment of leukemia and lymphoma. We previously show that both CS1-CAR T cells and CS1-CAR NK cells are effective in eradicating MM cells in vitro and in vivo (Chu et al., 2014, Leukemia and Chu et al., 2014, Clin. Cancer Res.). Both CS1 and CD38 are tumor-associated antigens expressed on the surface of MM cancer stem-like cells, suggesting that dual targeting of CS1 and CD38 may prevent relapse. Thus, we investigated the combination therapy with Dara and CS1-CAR NK cells for the treatment of relapsed MM. Our data showed that CD38 is highly expressed on the surface of both NK and MM cells. Dara induces NK cell activation, as Dara-treated NK cells display a higher capacity to produce IFN-gamma and increased cytotoxicity against MM, the latter of which correlated with augmented expression of the cytolytic gene, granzyme B. Mechanistically, we found that activation of NK cells by Dara is CD16-dependent. This is further evidenced by that Dara also significantly induces phosphorylation of NF-kB and STAT1, the two downstream mediators of CD16. Furthermore, Dara mediated cytotoxicity of NK cells against MM cells through antibody-dependent cell-mediated cytotoxicity (ADCC) against CD38-positive (e.g., MM1.S), but not CD38-negative (e.g., U266), which can be blocked by a CD16 blocking Ab. Dara-induced NK cell ADCC against CD38(+) MM MM1.S cells also leads to increased T cell proliferation and activation in a co-culture system including dendritic cells. However, Dara also induces apoptosis and fratricide in NK cells. This is evidenced by the data in vitro as well as our clinic data showing that Dara depletes NK cells in MM patients. Cleaved Caspase-3 and cleaved PARP-1were found increased in NK cells treated with Dara. Dara-induced apoptosis in NK cells is most likely also through an ADCC mechanism and Dara induces apoptosis in CD16(+) NK cells but not CD16(-) NK cells. Our data further show that Dara activates but does not induce apoptosis in CD38(-) NK cells. Thus, we hypothesize that the combination of Dara and CD38(-) CS1-CAR NK cells can show a synergistic effect on tumor eradication and prevention of MM relapse. Our data indeed demonstrated that the combination of CS1 CAR NK cells with CD38(-) NK cells but not with CD38+ NK cells shows a synergistic effect to eradicate MM cells. Interestingly, we also found that when compared to expanded CD38(+) NK cells, expanded CD38(-) NK cells have more cells, a better capacity of proliferation and survival, a higher potential of cytokine production, and higher cytotoxicity against MM cells.
Citation Format: Yufeng Wang, Yibo Zhang, Don Bnson, Michael Caligiuri, Jianhua Yu. Daratumumab combined with CD38(-) natural killer cells armed with a CS1 chimeric antigen receptor for the treatment of relapsed multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4617. doi:10.1158/1538-7445.AM2017-4617