Abstract 37: Anti-OX40 (MEDI6469) prior to definitive surgical resection in patients with head and neck squamous cell carcinoma
Authors: Bell R. Bryan , Leidner Rom S. , Duhen Rebekka A. , Ballesteros-Merino Carmen , Feng Zipei , Koguchi Yoshinobu , Bifulco Carlo B. , Curti Brendan D. , Urba Walter J. , Fox Bernard A. , Weinberg Andrew D. 
Published: December 2017

Abstract
Background: Head and neck squamous cell carcinomas (HNSCC) produce suppressive factors that impair the immune system, thus limiting effective antitumor immunity. OX40 is a member of the tumor necrosis factor (TNF) receptor family and its biologic activity leads to potent co-stimulation, which can enhance T-cell memory, proliferation and antitumor activity in patients with metastatic cancer. However, its effect on wound healing and the optimal timing of administration in relation to surgery to induce immune changes within the tumor microenvironment (TME) is not known.
Objectives: To determine the safety and peak immunologic activity of neoadjuvant anti-OX40 treatment administered prior to definitive surgical resection in patients with locoregionally advanced HNSCC.
Methods: Between January 2016 and July 2016, 10 patients with locoregionally advanced HNSCC were enrolled into this phase Ib neoadjuvant time course trial testing a murine antibody to OX40 (MEDI6469) administered 2 days, 1 week and 2 weeks prior to definitive surgical resection. In order to assess changes in the tumor microenvironment (TME), a tissue biopsy and peripheral blood samples were obtained prior to MEDI6469 infusion and tissue was also harvested at the time of surgical resection from the primary tumor site, metastatic and draining lymph nodes along with peripheral blood. Assessments of tumor infiltrating lymphocyte (TIL) populations were performed based on flow cytometry and fluorescent multiplex immunohistochemistry (mIHC); other circulating immunologic parameters that correlate with changes induced by MEDI6469 administration were also measured. These immune changes were assessed and compiled in a “cumulative suppression index,” which incorporates immunosuppressive elements within the tumor, such as FoxP3+ and PD-L1+ cells, to be correlated with clinical variables and outcome. Surgical complications were described using the Clavien-Dindo grading scale. Clinical trial information: NCT02274155.
Results: MEDI6469 administration was well tolerated and there were no grade 3 or 4 adverse events (AEs) attributable to anti-OX40 treatment. The toxicity profile was mild, most commonly consisting of low-grade fever prior to surgery, which was performed in all patients without delay. Postoperative grade 3 and 4 complications per Clavien-Dindo scale were observed in two patients. Immunologic changes were observed at all time courses with significant activation and proliferation of CD4+ and CD8+ central and effector memory T-cell populations in both the TME and circulation occurring between 12 and 19 days following MEDI6469 infusion. Ki67 was specifically induced in the TME and on peripheral blood PBMCs after MEDI6469 administration, returning to baseline at Day 55. Up-regulation of PD-L1 was also seen in the tumor post treatment in the majority of specimens. In the tumor, expression of CD39, ICOS and PD-1 is increased on CD4+ T cells in almost all patients and a recently identified tumor-reactive T-cell subset of CD39+CD103+CD8+ T cells, with resident memory phenotype, was increased in some patients.
Conclusion: Preoperative MEDI6469 administration prior to surgery is feasible and safe in patients with HNSCC and results in activation and proliferation of T cell populations and up-regulation of PD-L1 in tumor cells occurring between 12 and 19 days following infusion.
Citation Format: R. Bryan Bell, Rom S. Leidner, Rebekka A. Duhen, Carmen Ballesteros-Merino, Zipei Feng, Yoshinobu Koguchi, Carlo B. Bifulco, Brendan D. Curti, Walter J. Urba, Bernard A. Fox, Andrew D. Weinberg. Anti-OX40 (MEDI6469) prior to definitive surgical resection in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 37.