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

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.

Serum Levels of OX40 in Early and Late-Stage Oral Squamous Cell Carcinoma

“…Oberst et al demonstrated that the human OX40L IgG4P Fc fusion protein (MEDI6383) subdues the Tregs function of immunosuppression by inducing the activation of T-cells in vitro and in vivo models [ 21 ]. The current trial of OX40 agonist demonstrated an increase in TILs and improvement in the patients with an adequate safety profile [ 22 ]. However, the effect of immune checkpoint blockade therapy on OSCC is limited and the subtypes within the TILs and expression of immune cell subtypes should be also taken into account [ 23 ].…”

Impact of Immunotherapy on CD4 T Cell Phenotypes and Function in Cancer

“…Costimulatory receptors on T cells that have been targeted for immunotherapy of cancer include OX40, GITR and 4-1BB. Neoadjuvant anti-OX40 therapy in patients with head and neck squamous cell carcinoma led to increases of activated CD4 and CD8 T cells in both blood and tumors [ 51 ]. The initial results of therapy with an agonistic anti-GITR antibody indicates that it leads to reduction of regulatory CD4 T cells in both blood and tumors and would need to be combined with other immunotherapies, anti-PD-1 specifically, to attain clinical efficacy [ 52 ].…”

The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

“…However, the T cells made strong responses to the E6 and E7 proteins from human papilloma virus. Notably, these responses were exclusively found in the CD103 + CD39 + population of resident CD8 T cells (101), demonstrating that these cells are not restricted to mutated neoantigen reactivity. In B16 tumors in murine models, approximately half of the clonally expanded T cells in the tumor were reactive to the unmodified gp70 epitope that is shared in many murine tumors (43).…”

“…However, in addition to neoantigens, there are an array of tumor-associated antigens (100) and in some cases viral antigens that can be effective targets for T cells. For example, in a recent clinical study in head and neck cancer, CD8 + T cells in the tumor did not make measurable responses to any of the mutated neoantigens that were present in the cancer cells (101). However, the T cells made strong responses to the E6 and E7 proteins from human papilloma virus.…”