Combination immunotherapy before surgery may increase survival in people with head and neck cancer

CHAPEL HILL, North Carolina—Researchers conducting a clinical trial of immunotherapy drugs for people with head and neck squamous cell carcinomas (HNSCCs) found that patients responded better to a combination of two immunotherapies than patients who received just one immunotherapy drug.

The scientists also analyzed immune cells in each person’s tumor after one month of immunotherapy to see which type of immune cells were activated to fight their cancer, suggesting that some of the cells and targets they identified could help individualize treatment benefit.

The findings appeared March 13, 2025 in Cancer Cell.

HNSCCs occur in the oral cavity, pharynx, hypopharynx, larynx, nasal cavity and salivary glands and comprise the seventh most common cancer diagnosis worldwide. With an estimated 890,000 new cases and 450,000 deaths occurring annually, HNSCC accounts for roughly 4.5% of cancer diagnoses and deaths worldwide.

Current HNSCC treatments can be disfiguring and negatively impact a patient’s quality of life. Shrinking a tumor prior to surgery increases the chance that a surgeon can preserve a person’s tongue and voice box, which are important for speaking, breathing and swallowing.

“My group has conducted pre-operative trials in head and neck cancers for over 15 years, and the ability to shrink tumors with existing drugs prior to surgery has been relatively disappointing. While a recent trial has shown that single-drug immunotherapy provides a benefit, it only worked in a small number of patients,” said Robert L. Ferris, MD, PhD, executive director of UNC Lineberger Comprehensive Cancer Center.

“In our clinical trial, we compared two different combinations of immunotherapy drugs to using a single immunotherapy drug, and found that either combination regimen doubled or tripled the response rate versus the single immunotherapy, and led to a survival benefit. Up to a third of patients who received two drugs saw over 50 percent of their tumor disappear after only one month of treatment.”

Ferris started the research while on faculty at UPMC Hillman Cancer Center, Pittsburgh, then completed it after being appointed as the executive director of UNC Lineberger and system chief of oncology services at UNC Health in June 2024.

Others from the Ferris group included Lazar Vujanovic, PhD, of UPMC Hillman, as second corresponding author. Housaiyin Li and Dan P. Zandberg, MD, a graduate student and medical oncologist at UPMC Hillman, respectively, are the first authors.

The study randomly assigned 42 patients (one would later withdraw consent) to three immunotherapy treatment arms: nivolumab alone, nivolumab plus ipilimumab and nivolumab plus relatlimab. Both immunotherapy combinations appeared to perform equally well. The researchers attribute this to the drugs activating tumor-specific T lymphocytes, a type of immune T cell that specifically recognizes and attacks cancer cells. Even after surgical removal of a treatment-shrunken tumor, the T lymphocytes remain alive and circulating in patients’ bodies, providing surveillance that can increase long-term survival benefit.

“In this trial, we were able to specifically identify biological signatures that helped us decide which immunotherapy combination was best to use. The Lymphocyte Activation Gene-3, or LAG-3, protein was a good marker for some people while the CTLA-4 protein was a good marker for others,” Ferris said. “The immune status or markers a patient might have at diagnosis can help dictate which regimen is best to select for their treatment, and because of this marker’s promise, we have filed a patent for our diagnostic paradigm.”

Based on their discovery that the outcomes of the two different immunotherapy combinations appear similar, Ferris and his colleagues have extended this trial to include another 40 patients. They are also using a higher dose of relatlimab. They hope to see even better responses and longer survival in the expanded trial, which is ongoing.