LAUSR

Recruitment of immunosuppressive myeloid cells into the tumor microenvironment (TME) is a critical limitation to the efficacy of immune checkpoint inhibitors (ICIs) in patients with head and neck squamous cell carcinoma (HNSCC). In preclinical models, antibody blockade of Semaphorin 4D (SEMA4D, CD100) reduced function and recruitment of immunosuppressive myeloid cells within the TME. Importantly, combinations of anti-SEMA4D with ICIs enhanced T-cell activity and tumor regression. Pepinemab, an IgG4 humanized monoclonal antibody targeting SEMA4D, is currently being evaluated in window of opportunity, integrated biomarker trials to characterize immunomodulatory effects of treatment. SEMA4D exerts multifaceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin, restricting immune cell infiltration and promoting immunosuppressive activity of myeloid-derived cells. In preclinical in vitro and in vivo studies, blocking antibody to SEMA4D directly enhanced M1/M2 ratio and reduced both expression of chemokines that recruit MDSC and the ability of MDSC to suppress T-cell activity. SEMA4D antibody treatment simultaneously restored the ability of dendritic cells and cytotoxic T cells to infiltrate the TME and increased ratio of Teffector to Tregulatory cells. This coordinated shift from immunosuppression to tumoricidal activity complemented effects of other immunotherapies in syngeneic tumor models. At present, three biomarker-driven window of opportunity trials are recruiting patients with four resectable indications to investigate novel combinations of pepinemab with ICIs: 1) HNSCC (NCT03690986, n=36), 2) pancreatic ductal adenocarcinoma and colorectal cancer with resectable liver metastases (NCT03373188, n=32), and 3) metastatic melanoma (NCT03769155, n=36). Presurgical treatment cohorts include combinations of pepinemab with nivolumab and /or ipilimumab, single agents, or no treatment. Three to seven weeks later, surgically resected tumors are collected under the guidance of a pathologist for comparison of tumor infiltrates across treatment groups and with a predose tissue biopsy. Blood is collected for PK, PD, and additional correlative biomarker assessments. Correlative multiplex flow cytometric and immunohistochemistry panels have been established to phenotype cells in the TME and periphery; preliminary biomarker analysis will be presented. Additional objectives include evaluation of pathologic response and extension of the previously reported safety profile of pepinemab to additional ICI combination therapies. Twelve subjects, including two HNSCC patients, have been enrolled in these studies as of 01 Feb 2019. These trials will provide the first integrated clinical assessment of the use of anti-SEMA4D antibody to reprogram the TME. Citation Format: Elizabeth E. Evans, Gregory B. Lesinski, Terrence L. Fisher, Crystal Mallow, Brian Olson, Paul E. Clavijo, John E. Leonard, Desa Rae Pastore, Ernest S. Smith, Maurice Zauderer, Clint T. Allen, Michael Lowe, Ragini Kudchadkar, Christina Wu, Conor Steuer, Nabil F. Saba. Integrated biomarker trials to evaluate myeloid and lymphoid composition of HNSCC and solid tumors treated with pepinemab and combinations with checkpoint inhibitors [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A15.