Neoadjuvant anti-OX40 (MEDI6469) prior to surgery in head and neck squamous cell carcinoma.

Abstract

6011 Background: This phase Ib clinical trial was performed to investigate an agonistic murine antibody to OX40 (MEDI6469) at various dose intervals prior to definitive surgical resection in patients with head and neck squamous cell carcinoma (HNSCC). Methods: 17 patients with resectable stage III-IVA HNSCC (11 = HPV-; 7 = HPV+) received MEDI6469 0.4mg/kg x 3 doses administered on day 1, day 3-4 and day 5-6 of the study, followed by definitive surgical excision and neck dissection either 2 days, 1 week or 2 weeks after infusion of anti-OX40. Primary tumor, lymph nodes and peripheral blood (PB) were obtained at baseline and at the time of surgery to characterize the circulating and tumor infiltrating lymphocyte (TIL) cell populations based on flow cytometry (FC) and multiplex immunohistochemistry (mIHC) as well as whole transcriptome analysis via RNA-sequencing (seq). Results: MEDI6469 administration was well tolerated, surgery was not delayed, and there were no grade 3 or 4 adverse events related to MEDI6469 treatment. With a median follow up of 20 months, 13/17 patients are alive without disease. 4 patients had evidence of an immunological response to treatment on FC and mIHC that peaked between 12 and 19 days after MEDI6469 infusion and was characterized by: 1) increased Ki67+CD38+ICOS+ CD4+ and CD8+ memory T-cell populations in both the TME and PB, 2) increased expression of CD39, ICOS and PD-1 on CD4+ TIL (N = 10), and 3) increased frequency of tumor-reactive, tissue resident CD39+CD103+CD8+ T cells (N = 5). RNA-seq analysis of the primary tumor in a subset of patients (N = 7) revealed significant differences between immunological responders and non-responders in genes associated with MHC I-mediated antigen processing and presentation. Subsequent immune-subtype deconvolution analysis of the RNA data revealed all responders segregated with above median levels of CD39+CD103+CD8+ T cells, consistent with flow and mIHC. Conclusions: Preoperative MEDI6469 administration is safe and resulted in increased activation and proliferation of T cells within the tumor, peaking two weeks following infusion. Immunologic changes are associated with MHC I-mediated antigen processing machinery. Clinical trial information: NCT02274155.