Correlative and spatial biomarker analysis of a phase 1/2b study to evaluate pepinemab in combination with pembrolizumab for first-line treatment of patients with recurrent or metastatic head and neck cancer.
Authors: Evans Elizabeth E. , Fisher Terrence Lee , Mallow Crystal L. , Foster Amber , Leonard John E. , Chaney Marya F. , Mekhail Tarek , Seetharamu Nagashree , Steuer Conor Ernst , Saba Nabil F. , Adkins Douglas , Beck J. Thaddeus , Algazi Alain Patrick , Burtness Barbara , Baumgart Megan , Giampoli Ellen , Hager Steven Jeffrey , Chay Christopher H. , Spira Alexander I. , Zauderer Maurice 
Published: June 2024

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Background: Myeloid cells contribute to suppression of adaptive immunity within the TME and limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Semaphorin 4D (SEMA4D) signaling through its receptors (PlexinB1/B2, CD72) promotes recruitment and suppressive function of myeloid suppressor cells (MDSC). In preclinical and clinical studies, SEMA4D antibody blockade attenuated MDSC and increased penetration and organization of dendritic cells (DC) and T cells into tertiary lymphoid structures that enhanced activity of ICI. We hypothesize that SEMA4D blocking antibody pepinemab may regulate infiltration and crosstalk of immune cells in TME as a novel and complementary mechanism of immune enhancement when combined with immune checkpoint therapy. Methods: KEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of recurrent or metastatic HNSCC. Exploratory biomarker analyses were performed to evaluate spatial interactions of tumoral immune cells. Pre- and on-treatment tumor biopsies were collected and assessed by multiplex immunohistochemistry for up to 36 biomarkers/biopsy. Unbiased algorithms identified co-localization of markers for advanced cell phenotyping, density, spatial and proximity analysis. Biomarker results were then stratified by demographic and clinical outcome measures. Results: An increase in activated APC (HLA-DR+CD11c+ and HLA-DR+CD68+) and reduced density of MDSC (Arg1+CD14+ and ARG1+CD15+) was observed in patients with durable disease control. Interestingly, spatial analysis of tumor biopsies revealed that combination therapy induced the formation of highly organized immune aggregates, including a high density of activated B cells, DCs, CD4+ and CD8+ T cells, including stem-like CD8+TCF1+PD1+ T cells. Presence of immune aggregates increased in on-treatment compared to pre-treatment biopsies, even in HPV-negative and PD-L1 low tumors. Favorable spatial interactions between DC-1, CD8, CD4, and B cells was associated with PFS and disease control. Conclusions: Results suggest that combination therapy induced formation of highly organized lymphoid aggregates in HNSCC tumors, with a high density of activated B cells, DC and T cells. Together with similar observations indicating that combination immunotherapy with pepinemab induces mature lymphoid structures in tumors of patients with metastatic melanoma, provides evidence of treatment-induced biologic activity corresponding with disease control and suggests a novel and independent mechanism of pepinemab to enhance immune interactions and ICI activity. Clinical trial information: NCT04815720 .