Abstract 4557: BCMA-CD3 bispecific antibody PF-06863135: Preclinical rationale for therapeutic combinations

BCMA-CD3 bispecific antibody PF-06863135 is currently under evaluation in an ongoing Phase 1 clinical trial in relapsed/refractory (RR) multiple myeloma (MM) patients (NCT03269136). We showed previously that BCMA-CD3 bispecific has potent single agent activity in RR MM human bone marrow aspirates in vitro and in preclinical models of human myeloma (Panowski et al, MCT 2019). Herein we used in vitro assays, ex vivo MM patient 3D cultures, and in vivo efficacy models to study therapeutic combinations of PF-06863135 with immune checkpoint inhibitors, immunomodulatory drugs (IMiD), and gamma secretase inhibitors (GSI). Upregulation of immune checkpoints, such as programmed cell death protein-1 (PD-1) or programmed death ligand 1 (PD-L1) has been demonstrated downstream of response to CD3 bispecifics. While PF-06863135 is effective as a single agent in ex vivo 3D primary MM cultures (EC50 0.2 nM), PD-L1 was upregulated on myeloma cells. We combined PF-06863135 with anti-PD-1 in subcutaneous and orthotopic myeloma models MM.1S and MM.1S-PD-L1 in NSG mice engrafted with human T cells. PF-06863135 demonstrated single agent anti-tumor activity in the MM.1S models; however, in the MM.1S-PD-L1 model, PF-06863135 activity was blunted. When given in combination with an anti-PD-1 blocking antibody, the full thrust of the single agent anti-tumor activity of PF-06863135 was restored. Dysfunctional, senescent like T cells may emerge downstream of T cell immunotherapies. IMiDs, such as lenalidomide, are a standard of care therapy in MM and result in immunomodulatory effects on T cells leading us to hypothesize PF-06863135 mediated tumor growth inhibition could be enhanced by combining with lenalidomide. When PF-06863135 and lenalidomide were given in combination in the human T cell engrafted established orthotopic MM.1S and MOLP8 models, an even greater anti-tumor activity was observed as compared to either agent alone. These studies suggest that PF-06863135 activity can be augmented by combinations with immunomodulatory agents such as anti-PD-1 or lenalidomide. BCMA is shed from the surface of myeloma cells by gamma secretases, not only reducing cell surface target density but contributing to a soluble sink. When treated with GSI in vitro, myeloma cell surface BCMA expression increased concurrent with reduction in soluble/shed BCMA across a panel of myeloma and lymphoma cell lines expressing a range of BCMA. In cytotoxic T lymphocyte co-culture assays, the activity of PF-06863135 was potentiated by combining with GSI. Studies of the combination of PF-06863135 and GSI are ongoing in preclinical in vivo models of myeloma. Taken together, our preclinical studies provide insights into mechanisms of action and resistance for PF-06863135, which has potential for profound single agent activity that can be enhanced with therapeutic combinations. Citation Format: Katarzyna Karwacz, Andrea T. Hooper, Chao-Pei Betty Chang, Heike Krupka, Jeffrey Chou, Viola Lam, Ivana Djuretic, Javier Chaparro-Riggers, Puja Sapra. BCMA-CD3 bispecific antibody PF-06863135: Preclinical rationale for therapeutic combinations [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 4557.