Abstract 889: T cell help enhances anti-CD38-mediated NK cell ADCC of multiple myeloma despite expression of CD38 by NK cells

Abstract Anti-CD38 monoclonal antibodies such as daratumumab and isatuximab are effective therapeutic agents for some patients with multiple myeloma (MM) even though CD38 is expressed by B cells, monocytes and a significant subset of NK cells as well as MM cells. Treatment with anti-CD38 antibodies has been shown to deplete NK cells from the peripheral blood. This raises questions concerning the mechanisms of action of anti-CD38 as a treatment for MM such as NK cell mediated antibody dependent cellular cytotoxicity (ADCC). Since many NK cells express CD38, such NK cells could be susceptible to anti-CD38-induced fratricide, where CD38-expressing NK cells are targeted and eliminated. In previous studies in vitro, in animal model and in clinical correlative studies, we demonstrated that T cells play a key role in supporting NK cell viability and cytotoxicity following NK cell activation by anti-CD20 coated target cells. This T cell help is provided largely through IL2 production in the local microenvironment by CD4+ T cells. Here, we evaluated the role of T cell help in anti-CD38 mediated NK cell ADCC. Peripheral Blood Mononuclear Cells (PBMCs) were obtained from normal donors. T cells were depleted and added back to the PBMCs in known numbers to create PBMCs with controlled numbers of T cells. These PBMCs were cultured with MM.1S myeloma cells for 1, 3, or 7 days with and without anti-CD38. The presence of T cells had limited impact on tumor cell numbers or NK cell phenotype in the absence of anti-CD38 confirming modest direct anti-MM effect of T cells in this culture system. CD38 expression by NK cells was decreased after culture with anti-CD38 under all conditions. NK mediated ADCC was observed despite loss of NK cell CD38. This ADCC was dependent on T cell help. MM cells were reduced by day 3 and were largely eliminated by day 7 in samples treated with anti-CD38. Greater anti-MM effects were seen with PBMCs that contained larger numbers of T cells while ADCC was less apparent in samples with fewer numbers of T cells. At day 7, IL2 restored the longer-term anti-MM effect of anti-CD38 in the absence of T cells. A T cell dependent increase in NK cell numbers was also seen at day 7. We conclude that anti-CD38 can induce NK cell mediated ADCC of MM cells despite loss of CD38 expression by NK cells suggesting down-modulation of CD38 on NK cells as opposed to fratricide of CD38-expressing NK cells. T cell help, likely mediated in large part by local production of IL2, enhances anti-CD38-induced NK cell activation, viability and ADCC. These data indicate NK cell ADCC, enhanced by local T cell help, may be an important mechanism of action for anti-CD38 in MM. Citation Format: Reza Amani, Jyoti Arora, George J. Weiner. T cell help enhances anti-CD38-mediated NK cell ADCC of multiple myeloma despite expression of CD38 by NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 889.