2020 Head and Neck Cancers Symposium: Immune Restorative Agent May Boost Immunotherapy Response in Advanced Head and Neck Cancer

Immune modulation with checkpoint inhibitors has shown benefit in advanced head and neck squamous cell carcinoma, but responses have been limited to a small number of patients. According to data presented by Gregory T. Wolf, MD, FACS, Professor Emeritus in the Department of Otolaryngology-Head and Neck Surgery at the University of Michigan Medical Center, at the 2020 Multidisciplinary Head and Neck Cancers Symposium (Abstract 2), an additional agent with beneficial immune modulatory effects could help overcome tumor-mediated immunosuppression.

As Dr. Wolf explained, immune impairment in patients with head and neck cancer is multifaceted, occurs early in disease, persists after treatment, and is associated with poor outcomes. Given the “very small percentage” of patients who have positive responses to checkpoint inhibitors, said Dr. Wolf, additional agents with beneficial immune effects are needed.


In the phase II randomized trial, researchers tested an agent called IRX-2, a primary cell–derived immune restorative consisting of human cytokines that act on multiple cell types to overcome tumor-mediated immunosuppression. Sixty-four patients were randomly assigned to arm A, which consisted of treatment with an initial dose of cyclophosphamide (300 mg/m2) 3 weeks prior to surgery followed by 10 days of regional perilymphatic IRX-2 cytokine injections, and daily indomethacin, zinc, and omeprazole. The 32 patients in arm B received an identical regimen, but without the IRX-2 cytokines. The researchers collected pre- and posttreatment specimens from 39 patients and analyzed changes in T-cell subsets in the tumor-infiltrating lymphocytes population in the tumor microenvironment.

Patients exhibiting an increase in CD8-positive tumor-infiltrating lymphocytes infiltrate score of at least 10 cells/mm2 were designated as “immune responders,” said Dr. Wolf. This definition was derived from a previous study of 228 patients with oral cavity cancer that showed a 15% decrease in the risk of death with a similar increase in T-cell density.

Treatment in arm A was associated with significant posttreatment increases in CD8-positive infiltrates (= .01) compared to the control group, which only demonstrated a trend for higher tumor-associated macrophages (CD68-positive, = .11). Results showed 14 (74%) of 19 patients receiving the IRX-2 regimen were immune responders, compared to 4 (31%) of 15 patients in the control arm.

Because five of six p16-positive patients were randomly assigned to the experimental arm, investigators repeated the analysis of tumor-infiltrating lymphocytes after removing the p16-positive patients. Changes were “even more striking” for both CD8-positive infiltrates and overall tumor-infiltrating lymphocytes, said Dr. Wolf. In patients with p16-negative cancers, significant increases in CD8-positive, CD20-positive, and overall tumor-infiltrating lymphocytes were evident in the experimental arm.

The study authors concluded, “The findings demonstrate significant increases in T cells infiltrating the primary tumor after perilymphatic IRX-2 injections that correlated with decreases in measured tumor size. Three-quarters of patients showed significant immune responses, suggesting that the IRX-2 regimen could be considered for combination with other immune modifiers such as checkpoint inhibitors. The results also suggest that p16 status could be a useful marker for patient selection.”

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