Abstract 6007: Neoadjuvant pepinemab enhances DC function associated with mature tertiary lymphoid structures and activity of immune checkpoint blockade in patients with metastatic melanoma

Abstract Neoadjuvant treatment with immune checkpoint blockade (ICB) improves clinical benefit relative to adjuvant therapy in multiple types of cancer. Window of opportunity studies employing neoadjuvant treatment permit integrated assessments of pathologic response along with assessments of treatment effects and mechanisms of resistance in the tumor microenvironment. Resistance mechanisms including immune exclusion and myeloid suppression have been shown to be regulated by semaphorin 4D (SEMA4D) in preclinical and clinical studies. A neoadjuvant window of opportunity study was designed to evaluate activity and efficacy of pepinemab, SEMA4D blocking antibody, combined with nivolumab (nivo) and/or ipilimumab (ipi) in patients with surgically resectable metastatic melanoma. Consenting patients with resectable stage III melanoma received neoadjuvant nivo alone, pepinemab/nivo, pepinemab/ipi, or pepinemab/nivo/ipi (NCT03769155). Patients underwent surgical resection following six weeks of immunotherapy. In separate studies conducted at University of Texas MD Anderson Cancer Center, patients received neoadjuvant treatment with nivo or nivo/ipi. Surgical tissue underwent high dimensional immune analysis using multiparametric flow cytometry, multiplex immunohistochemistry and Nanostring RNAseq and GeoMX imaging. Pepinemab in combination with nivo (either alone or with ipi) significantly increased tumor-infiltrating B cells and CD4+ T cells within surgical tissue, versus surgery or nivoalone. Compared to nivo alone, pepinemab plus nivo significantly influenced REACTOME pathways involved in degradation of extracellular matrix and signaling by Rho GTPases. Significant changes in DC activation markers including Flt3 (p=0.03) and cDC2 marker CD163 (p=0.0071), and the the Flt3/Wnt pathway correlated with pepinemab treatment and pathologic response. Multiplex IHC revealed tertiary lymphoid structures (TLS) within the tumor bed following treatment and were increased in patients who did not suffer tumor recurrence. TLS identified in biopsies of patients treated with pepinemab in combination with ICB were larger and more mature, containing high density of activated DCs and follicular DCs, follicular B cells, and Tfh cells expressing CXCR5, characteristic of germinal centers. Mature TLS were significantly increased in the triple combination compared to doublets or nivo alone. Increased density and maturity of TLS and increased T cell clonality correlated with pepinemab treatment and clinical benefit. All patients receiving triple combination therapy (8/8) were recurrence-free at 24 months with mature TLS in the resected tumors (6/6). Pepinemab represents a novel strategy to boost dendritic cell infiltration, activation, and organization of functional TLS to overcome limitations of ICB. Citation Format: Elizabeth E. Evans, Crystal Mallow, Terrence L. Fisher, Ayana Ruffin, Elaine Gersz, Maria Scrivens, Elizabeth Tuttle, Vuyani Matsenjwa, Ellen Giampoli, Manoj Chelvanambi, Brenda Melendez, Florentia Dimitrou, Alexander J. Lazar, Jennifer Wargo, Michael Lowe, Chrystal M. Paulos, Gregory B. Lesinski, Maurice Zauderer. Neoadjuvant pepinemab enhances DC function associated with mature tertiary lymphoid structures and activity of immune checkpoint blockade in patients with metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6007.