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

• Published in: Nature communications 2021-02, Vol.12 (1), p.1047-1047, Article 1047
• Main Authors: Duhen, Rebekka, Ballesteros-Merino, Carmen, Frye, Alexandra K., Tran, Eric, Rajamanickam, Venkatesh, Chang, Shu-Ching, Koguchi, Yoshinobu, Bifulco, Carlo B., Bernard, Brady, Leidner, Rom S., Curti, Brendan D., Fox, Bernard A., Urba, Walter J., Bell, R. Bryan, Weinberg, Andrew D.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 14/63; 38/23; 631/250/251; 631/67/1536/1665; 692/4028/67/1059/2325; 692/4028/67/580; Agonists; Antibodies; Antigens; Biomarkers; Biopsy; Blood; Cancer; CD103 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Proliferation; Clinical trials; Clone Cells; Costimulator; Disease-Free Survival; Epitopes - immunology; Head & neck cancer; Health services; Human papillomavirus 16 - physiology; Humanities and Social Sciences; Humans; Immune checkpoint; Immunotherapy; Kaplan-Meier Estimate; Lymphocyte Activation - immunology; Lymphocyte Subsets - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; multidisciplinary; Neoadjuvant Therapy - adverse effects; Patients; Peripheral blood; Phenotyping; Receptors, Antigen, T-Cell - metabolism; Receptors, OX40 - antagonists & inhibitors; Receptors, OX40 - metabolism; Science; Science (multidisciplinary); Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - blood; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - therapy; Stromal Cells - metabolism; Surgery; Tumor necrosis factor; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21383-1

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. Different neoadjuvant therapies have been proposed to improve immunotherapy for cancer treatment. Here, the authors perform a phase Ib clinical trial where an agonist OX40 antibody provided prior to surgery is well tolerated and increases proliferation and activation of tumor antigen-specific T cells in head and neck cancer patients.