Abstract 5179: Isatuximab based combinations induce potent tumor growth inhibition in pre-clinical models of multiple myeloma and acute lymphocytic leukemia
Authors: Zhu Chen , Nicolazzi Celine , de Velde Helgi Van , Wiederschain Dmitri , Sidhu Sukhvinder , Chiron Marielle 
Published: September 2020

Abstract
CD38 is highly expressed in many hematological malignancies such as multiple myeloma (MM) and acute lymphocytic leukemia (ALL) and can be targeted by antibody-based therapy. Isatuximab, an anti-CD38 IgG1 monoclonal antibody has promising clinical activity in relapsed/refractory multiple myeloma patients. It induces tumor cells death via Fc-mediated cytotoxic effects, direct cancer cell killing, and inhibition of CD38 enzymatic activity.
We investigated the mechanisms of action (MoA) of isatuximab against MM and ALL in vitro and evaluated its in vivo pharmacological potency in combination with standard therapies for these two hematologic malignancies. Isatuximab preferentially induced robust antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) in both MM and ALL cell lines. Cancer cells with particularly high level of CD38 were also susceptible to apoptosis or CDC induced by isatuximab. In vitro, isatuximab displayed time- and dose-dependent inhibitory effect on CD38 enzymatic activity shown in LP-1 myeloma cells, suggesting that it could alleviate immunosuppressive effects of CD38-mediated adenosine synthesis in the tumor microenvironment.
In vivo efficacy studies were conducted in mouse xenograft models. The in vivo efficacy of isatuximab in combination with the immunomodulatory drugs (IMiDs) pomalidomide or lenalidomide that are standard of care in MM was evaluated. Each combination increased the inhibition of tumor growth (T/C) compared with isatuximab or IMiDs treatment alone. Combination of isatuximab with either bortezomib or carfilzomib, two proteasome inhibitors that are widely used in MM, significantly improved their anti-tumor activity versus each agent alone. Isatuximab also improved tumor growth inhibition mediated by alkylating agent melphalan.
Similarly, isatuximab enhanced the activity of different chemotherapies in an ALL tumor model. Its combination with vincristine, cytarabine or cyclophosphamide enhanced antitumor activity translating into a higher number of tumor-free survivors (TFS).
These results document the unique MoA of isatuximab, primarily through ADCC and ADCP, and its robust antitumor activity as a single agent and in combination with standard of care treatments used in these hematological malignancies.
ChemotherapyMM or T-ALL xenograft modelT/C IsatuximabT/C ChemotherapyT/C combinationPomalidomideMOLP-862%54%34%LenalidomideRPMI-822647%76%24%BortezomibNCI-H92928%26%0 %carfilzomibNCI-H92968%44%6%MelphalanLP-167%13%8%VincristineDND4141% no TFS0% no TFS0% 5/6 TFSAra-CDND4141% no TFS0% 3/6 TFS0% 6/6 TFScyclophosphamideDND4110% 4/7 TFS0% 4/7 TFS0% 7/7 TFS
Citation Format: Chen Zhu, Celine Nicolazzi, Helgi Van de Velde, Dmitri Wiederschain, Sukhvinder Sidhu, Marielle Chiron. Isatuximab based combinations induce potent tumor growth inhibition in pre-clinical models of multiple myeloma and acute lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5179.