Background: Cancer immunotherapy is an evolving treatment that boosts the immune system to recognize and destroy cancer cells. 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 a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and anti-tumor activity in patients with metastatic cancer.
Objectives: To determine the safety and immunologic activity of anti-OX40 treatment administered prior to definitive surgical resection in patients with locoregionally advanced HNSCC.
Methods: This is a phase Ib clinical trial using a murine antibody to OX40 (MEDI6469) at various time intervals prior to definitive surgical resection of patients with HNSCC. The interval between MEDI6469 doses and resection will allow for determination of the effect of MEDI6469 on the tumor infiltrating lymphocyte (TIL) composition over time and will ensure patient safety in administering MEDI6469 preoperatively. After the time-course portion of the trial, an expansion cohort of up to 35 additional patients will be enrolled at the safe pre-operative dosing interval found to have the most promising immune response measured in peripheral blood and within tumors. The primary endpoint is safety. In addition, tumor tissues and peripheral blood are being obtained for exploratory immunologic end points including measurements of tumor infiltrating immune cell populations based on flow cytometry, multispectoral imaging, immunohistochemistry, as well as other circulating immunological parameters that may correlate with changes induced by MEDI6469 administration. Enrollment is ongoing. Clinical trial information: NCT02274155
Results: The time course portion of the trial has completed enrollment. MEDI6469 administration was well tolerated and there were no grade 3 or 4 adverse events related to anti-OX40 treatment. The toxicity profile was mild, most commonly consisting of low-grade fever prior to surgery. Immunologic changes have been observed at all time courses with significant proliferation of CD4+ and CD8+ central and effector memory T-cell populations, both in the tumor microenvironment and circulation. The peak of activation was observed between 12 and 19 days following MEDI6469 infusion. Among other activation markers such as ICOS, PD-1 and CD38, Ki67 is specifically induced on peripheral blood PBMC’s and in the TIL after MEDI6469 administration, returning to baseline at Day 55 in the periphery. In the tumor, CD39 is induced on CD4+ T cells in almost all subjects and a subpopulation of CD39+/CD103+ CD8+ T cells is strongly increased in a subset of subjects. Enrollment in the expansion cohort is ongoing.
Conclusion: Preoperative MEDI6469 administration prior to surgery is feasible in patients with HNSCC and results in robust proliferation of T cell populations that peak between 12 and 19 days following infusion.