Biopsy; CD8-Positive T-Lymphocytes; Cell Proliferation; Clone Cells; Disease-Free Survival; Epitopes; Human papillomavirus 16; Humans; Kaplan-Meier Estimate; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Neoadjuvant Therapy; Receptors, Antigen, T-Cell; Receptors, OX40; Squamous Cell Carcinoma of Head and Neck; Stromal Cells; oregon; portland; chiles; genomics
Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRβ sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.
Earle A. Chiles Research Institute
Duhen, Rebekka; Ballesteros-Merino, Carmen; Frye, Alexandra K; Tran, Eric; Rajamanickam, Venkatesh; Chang, Shu-Ching; Koguchi, Yoshinobu; Bifulco, Carlo; Bernard, Brady; Leidner, Rom; Curti, Brendan; Fox, Bernard A; Urba, Walter; Bell, Richard Bryan; and Weinberg, Andrew D, "Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells." (2021). Articles, Abstracts, and Reports. 4422.