Anti-Cd38/Cd28xcd3 Trispecific T Cell Engager Induces Proliferation Of Primary T Cells And Mediates Potent Killing Of Primary Malignant Plasma Cells Isolated From Multiple Myeloma Bone Marrow Aspirates.

Abstract Despite recent breakthrough in the treatment of multiple myeloma (MM) relapses are frequent, highlighting the need for novel approaches. Here we describe a novel anti-CD38/CD28xCD3 trispecific T cell engager (TCE) that targets CD38 expressed by malignant plasma cells and activates T cells by engaging CD3 and CD28 (1). Using bone marrow (BM) aspirates from MM patients, we confirmed that binding to malignant plasmocytes is primarily driven by the expression of CD38 and showed ex vivo that CD38/CD28xCD3 TCE induces a dose-dependent proliferation of CD4+ and CD8+ effector T cells. We also showed that MM patients' primary T cells were stimulated by CD38/CD28xCD3 TCE resulting in RPMI 8226 MM cell line lysis in co-culture assays. Killing of tumor cells was accompanied by MM effector CD8+ T cell degranulation and immunostimulatory cytokine production (IFN-γ and TNF-α). Finally, using MM patients' total BM cells, we showed that CD38/CD28xCD3 TCE induced the activation and cytokine production by cytotoxic CD8+ T cells and the CD38-dependent depletion of autologous primary malignant plasmocytes. Importantly, treatment of total BM cells with CD38/CD28xCD3 TCE also led to a CD38-dependent depletion of immunosuppressive myeloid derived suppressor cells (MDSC) that express CD38. Overall, these data show that CD38/CD28xCD3 trispecific TCE is active against primary myeloma cells and support the current evaluation of this next generation anti-CD38 multi-specific antibody in phase I clinical trial in patients with relapsed/refractory MM. (1) Wu, L., Seung, E., Xu, L. et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer 1, 86-98 (2020). Citation Format: Nizar El-Murr, Sahar Kassem, Nadège Carrié, Christophe Henry, Angela Virone-Oddos, Zhi-yong Yang, Dmitri Wiederschain, Helgi Van de Velde, Marielle Chiron, Ludovic Martinet. Anti-CD38/CD28xCD3 trispecific T cell engager induces proliferation of primary T cells and mediates potent killing of primary malignant plasma cells isolated from Multiple Myeloma bone marrow aspirates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1887.