Abstract 3283: GEN1046 (DuoBody®-PD-L1x4-1BB) in combination with PD-1 blockade potentiates anti-tumor immunity

Abstract GEN1046 (DuoBody®-PD-L1x4-1BB) is an investigational, potential first-in-class bispecific immunomodulatory antibody designed to elicit an anti-tumor immune response by simultaneous and complementary blockade of PD-L1 on tumor or immune cells and conditional 4-1BB stimulation on T cells and NK cells. Previously, we described encouraging preclinical and early clinical activity of GEN1046 (Muik, et al., 2022, Cancer Discovery). We hypothesized that combining GEN1046 with PD-1 blockade would further potentiate anti-tumor activity through distinct and complementary immune modulatory effects. Addition of an anti-PD-1 agent would free up PD-L1 for binding to GEN1046, thus promoting PD-L1-dependent 4-1BB conditional agonism, while maintaining complete blockade of the PD-1 pathway by inhibiting interactions with both PD-L1 and PD-L2. ​Here we provide preclinical evidence supportive of therapeutic synergy by the combination of GEN1046 and anti-PD-1 and describe the mechanisms of enhanced anti-tumor immunity elicited by the combination. In in vitro studies, combining GEN1046 with an anti-PD-1 agent potentiated cytokine release in mixed lymphocyte reaction assays (using either unstimulated T cells or T cells exhausted by repeated CD3/CD28 co-stimulation) and enhanced T-cell expansion and cytokine secretion in antigen-specific proliferation assays compared to each single agent. In in vivo studies in mice bearing syngeneic subcutaneous MC38 tumors, the combination of an anti-mouse PD-L1x4-1BB bispecific antibody with anti-mouse PD-1 potentiated anti-tumor activity with significant enhancement of survival (P≤0.001) and durable, complete tumor regressions (CR) in 7/10 mice compared to no CR observed with either single agent, suggesting therapeutic synergy with the combination. The combination treatment elicited long-lasting immune memory response, as animals with CR were protected from tumor outgrowth upon rechallenge with MC38 cells. Mechanistically, animals treated with the combination showed a trend for ≥1.5-fold increase in the average density of CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs), as well as proliferating (Ki67+) and cytotoxic (GZMB+) CD8+ TILs relative to each single agent, consistent with an amplified anti-tumor immune response. Together, these preclinical results suggest that combining GEN1046-induced conditional 4-1BB stimulation with complete PD-1 blockade can improve the anti-tumor immune response via distinct and complementary immune modulatory effects. The combination of GEN1046 with pembrolizumab is currently being investigated in ongoing clinical studies in patients with advanced NSCLC, who are treatment-naïve (NCT03917381) or have progressed on prior CPI-containing therapy (NCT05117242). Citation Format: Michela Capello, Angelica Sette, Theo Plantinga, Vanessa Spires, Kristina Nuermberger, Jordan Blum, Alexander Muik, Carol Costa Sa, Omar Jabado, Saskia Burm, Aras Toker, Sina Fellermeier-Kopf, Tahi Ahmadi, Brandon Higgs, Suzana Couto, Özlem Türeci, Mark Fereshteh, Ugur Sahin, Maria Jure-Kunkel, Nora Pencheva. GEN1046 (DuoBody®-PD-L1x4-1BB) in combination with PD-1 blockade potentiates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3283.