Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells

Rebekka Duhen (), Carmen Ballesteros-Merino, Alexandra K. Frye, Eric Tran, Venkatesh Rajamanickam, Shu-Ching Chang, Yoshinobu Koguchi, Carlo B. Bifulco, Brady Bernard, Rom S. Leidner, Brendan D. Curti, Bernard A. Fox, Walter J. Urba, R. Bryan Bell and Andrew D. Weinberg ()
Additional contact information
Rebekka Duhen: Earle A. Chiles Research Institute, Providence Cancer Institute
Carmen Ballesteros-Merino: Earle A. Chiles Research Institute, Providence Cancer Institute
Alexandra K. Frye: Earle A. Chiles Research Institute, Providence Cancer Institute
Eric Tran: Earle A. Chiles Research Institute, Providence Cancer Institute
Venkatesh Rajamanickam: Earle A. Chiles Research Institute, Providence Cancer Institute
Shu-Ching Chang: Medical Data Research Center, Providence Saint Joseph’s Health
Yoshinobu Koguchi: Earle A. Chiles Research Institute, Providence Cancer Institute
Carlo B. Bifulco: Earle A. Chiles Research Institute, Providence Cancer Institute
Brady Bernard: Earle A. Chiles Research Institute, Providence Cancer Institute
Rom S. Leidner: Earle A. Chiles Research Institute, Providence Cancer Institute
Brendan D. Curti: Earle A. Chiles Research Institute, Providence Cancer Institute
Bernard A. Fox: Earle A. Chiles Research Institute, Providence Cancer Institute
Walter J. Urba: Earle A. Chiles Research Institute, Providence Cancer Institute
R. Bryan Bell: Earle A. Chiles Research Institute, Providence Cancer Institute
Andrew D. Weinberg: Earle A. Chiles Research Institute, Providence Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21383-1

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