Immune-Restorative Agent May Boost Immunotherapy Response in Advanced Head and Neck Cancer

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Immune modulation with checkpoint inhibitors has shown beneficial effects in advanced head and neck squamous cell carcinoma, but responses have been limited to a small number of patients. According to data presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium, however, an additional agent with beneficial immune-modulatory effects may help to overcome tumor-mediated immunosuppression.1

Preliminary analysis of the phase II randomized study found increased T cells infiltrating the primary tumor in patients with surgically resected, oral cavity carcinoma after injection with an agent called IRX-2. Approximately three-quarters of patients randomly assigned to the experimental arm showed significant immune responses, the study authors reported.

Gregory T. Wolf, MD, FACS

Gregory T. Wolf, MD, FACS

“In the experimental arm, the neoadjuvant IRX-2 immune restoration was associated with significant increases in CD8-­postive tumor-infiltrating lymphocytes, particularly in patients with p16-negative oral cavity cancer,” said Gregory T. Wolf, MD, FACS, Professor Emeritus, Department of Otolaryngology–Head and Neck Surgery at the University of Michigan Medical Center, Ann Arbor. “These findings provide rationale for potential combinations of neoadjuvant IRX-2 with checkpoint inhibitors.”

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, he said, additional agents with beneficial immune effects are needed.

Study Details

For this study, Dr. Wolf and colleagues tested IRX-2, a primary cell–derived immune-restorative agent consisting of human cytokines (predominantly interleukin-2) that act on multiple cell types to overcome tumor-mediated immunosuppression. A randomized phase II trial was conducted of the IRX-2 regimen 3 weeks prior to surgery, consisting of an initial dose of cyclophosphamide (300 mg/m2), followed by 10 days of regional perilymphatic IRX-2 cytokine injections, and daily indomethacin, zinc, and omeprazole (arm A), compared with the identical regimen without the IRX-2 cytokines (arm B). A total of 96 evaluable patients with resectable oral cavity carcinoma were randomly assigned (2:1) to one of the two study arms. The researchers collected pre- and posttreatment specimens from 39 patients (32 with all data points) and analyzed changes in T-cell subsets in the population with tumor-infiltrating lymphocytes in the tumor microenvironment.

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

Key Findings and p16 Status

As Dr. Wolf reported, the experimental arm (arm A) was associated with significant posttreatment increases in CD8-­positive infiltrates (P = .01) compared with the control group, which demonstrated a trend for higher tumor-associated macrophages (CD68-positive, P = .11). Results showed 14 of 19 patients (74%) receiving the IRX-2 regimen were immune responders, compared with 4 of 13 patients (31%) in the control arm.

The findings also suggest that p16 status could be a useful marker for patient selection. “These cancers tend to be more aggressive than oropharyngeal cancers,” said Dr. Wolf, who noted that p16 expression in the oral cavity does not necessarily correlate with human papillomavirus status. “We think p16 expression may represent a separate variant of oral cavity cancer.”

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

“We’re continuing to gather longer follow-up data on this trial to determine the correlations of changes in tumor-infiltrating lymphocytes with clinical outcomes,” Dr. Wolf concluded.

Potential Surrogate Markers

“The findings of potential surrogate markers are intriguing, and a phase III study may be warranted.”
— Tanguy Y. Seiwert, MD

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Moderator of the session, Tanguy Y. Seiwert, MD, Director of the Head and Neck Cancer Oncology Disease Group and Assistant Professor of Oncology at Johns Hopkins University, Baltimore, called the findings of potential surrogate markers “intriguing” and suggested a phase III study may be warranted. “The question of surrogate markers is a very important one,” added Dr. Wolf. “We included p16 because its expression may be a marker for patients with oral cavity cancer who might not benefit from immunotherapy.”

Dr. Wolf continued: “In a preclinical murine model, we’ve seen synergism with the combination of checkpoint inhibitors and IRX-2. The next step could be a phase II trial to see whether we can increase response rates while determining if surrogate markers  can guide therapy.” 

DISCLOSURE: Dr. Wolf has received honoraria from Regeneron; served on advisory boards for Merck and Regeneron; and has received institutional research funding from Brooklyn Immunotherapeutics, who sponsored the clinical trial. Dr. Seiwert reported no conflicts of interest.


1. Wolf GT, Liu S, Bellile E, et al: Immune modulation in a randomized trial of neoadjuvant IRX-2 regimen in patients with stage II-IV squamous cell carcinoma of the oral cavity: INSPIRE trial (NCT02609386) interim analysis. 2020 Multidisciplinary Head and Neck Cancers Symposium. Abstract 2. Presented February 27, 2020.