Abstract LB-C007: Enhancing immune interactions in tumor with pepinemab SEMA4D blocking antibody

Abstract Dendritic cells (DC) play critical and decisive roles in determining the outcome of immune responses in the TME. Strategies to recruit and activate DC have the potential to enhance immunotherapy. Pepinemab, semaphorin 4D (SEMA4D) blocking antibody, reversed myeloid suppression and promoted infiltration of activated DC and T cells into the TME in preclinical and clinical studies. In patients with surgically resectable metastatic melanoma (NCT03769155), neoadjuvant treatment with combination of pepinemab plus immune checkpoint inhibitors (ICI) increased density of mature lymphoid aggregates (mLA) that contain high density of activated HLA-DR+ DCs, FDC, follicular B cells, and Tfh cells expressing CXCR5, characteristic of germinal centers in tertiary lymphoid structures (TLS). Beneficial changes in TME correlated with pathologic response and prolonged recurrence free survival. New data demonstrates that facilitating interactions between DC and CD4 T cells is associated with improved response in ICI-resistant tumors. Pepinemab in combination with pembrolizumab was evaluated as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC (KEYNOTE-B84, NCT04815720). Screening and on-treatment tumor biopsies were evaluated using multiplex immunohistochemistry. Comparison of matched biopsy pairs before and after treatment indicated that mLA were induced by treatment and associated with disease control. Within the TME, a marked shift from myeloid suppression to activated cDC1 coupled with increased density of CD4+ T cells was observed in responders, which favored PD-L1 low (CPS 1-19) tumors compared to PD-L1 high (CPS ≥20). Combination treatment with pepinemab approximately doubled ORR, PFS and OS (25%, 7 and 16.3 months, respectively) in patients with PD-L1 low tumors, who typically do not respond well to ICI. Consistent with these observations, adoptive transfer of ex vivo expanded DC-1 enhanced effects of SEMA4D-blocking antibody in preclinical ICI-resistant models. This resulted in improved DC trafficking to draining lymph nodes and, importantly, induced tumor regression in both target and distant tumors. Responses were associated with increased frequency of IFN-gamma secreting CD4+ T cells and depletion of CD4+ T cells completely abrogated responses. Pepinemab represents a novel strategy to boost dendritic cell infiltration, activation, and organization of functional TLS to overcome limitations of immune checkpoint therapies. When combined with ICI, pepinemab induced de novo formation of TLS that correlated with clinical benefit, even in poorly immunogenic tumors that do not respond well to ICI, including PD-L1 low HNSCC. Citation Format: Elizabeth E. Evans, Crystal Mallow, Holm Bussler, Terrence L. Fisher, Saurabh Garg, Colin Snyder, Elaine Gersz, Maria Scrivens, Renee Kirk, Malgorzata Gil-Moore, Ellen Giampoli, Brian J. Czerniecki, Conor Steuer, Michael Lowe, Gregory B . Lesinski, Chrystal M. Paulos, Nabil Saba, Maurice Zauderer. Enhancing immune interactions in tumor with pepinemab SEMA4D blocking antibody [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C007.