A New Era of Preoperative Combination Immunotherapy for Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with approximately 890,000 new cases and 450,000 deaths annually. It can arise in the oral cavity, pharynx, hypopharynx, larynx, nasal cavity, and salivary glands, seriously affecting quality of life. Surgery and other current treatments often cause disfigurement and loss of function. Shrinking tumors before surgery may therefore help preserve vital structures such as the tongue or voice box.

Although immunotherapy alone has shown promise in recent years, it has been effective in only a limited number of patients. However, a new study published on March 13, 2025, in Cancer Cell examined neoadjuvant treatment (to shrink tumors before surgery) and found that combining two immunotherapy drugs may substantially improve response compared with immunotherapy alone.

Study Methods and Results

Researchers randomly assigned 42 patients with stage II / IVa head and neck squamous cell carcinoma to three regimens:

• Nivolumab + Ipilimumab

• Nivolumab + Relatlimab

• Nivolumab alone

Most participants were HPV-negative and had tumors that could be surgically removed.

Both combinations were observed to be equally effective. Researchers analyzed tumor tissue after treatment to determine which immune cells had been activated. Findings showed that the combinations activated tumor-specific T lymphocytes that directly targeted cancer cells.

Effectiveness was classified by pathological tumor response (pTY):

• pTY-0 (≥91% viable tumor),
• pTY-1 (51-90% viable tumor), and
• pTY-2 (≤50% viable tumor).

HPV status and PD-L1/LAG-3 expression were also analyzed, but no significant association with pathological response was found.

Notable Findings:

• Treatment with two immunotherapy drugs produced 2 to 3 times higher pathological tumor response rates (≤50% viable tumor) than a single drug:

  • Nivolumab + Ipilimumab: 36.4%
  • Nivolumab + Relatlimab: 26.7%
  • Nivolumab alone: 8.4%

• In one-third of patients,more than 50% of the tumor disappeared after just one month of treatment.

• When tumors were surgically removed after treatment, activated T cells continued circulating in the body, and patients were thereby observed to gain a long-term survival advantage.

Can Treatment Selection Be Personalized?

Researchers found that certain biomarkers could help identify the most suitable combination. For example:

• The LAG-3 proteinwas a useful marker for some patients.

• The CTLA-4 proteinwas identified as a more suitable target in other groups.

The authors stated that immunological markers could play a crucial role in treatment selection and that they had filed a patent application for this approach as a diagnostic paradigm.

Conclusion and Commentary

These findings appear different from earlier head and neck immunotherapy trials and suggest that its limited ability to shrink tumors before surgery might be overcome.

The researchers plan to expand the trial by enrolling another 40 patients. In this new group, they aim to use higher doses of Relatlimab to achieve stronger responses and longer survival.

This study may be an important step toward improving immunotherapy effectiveness in head and neck cancer. Personalized approaches may eventually help patients achieve better responses and survival.

In conclusion, the limited effectiveness of single-agent immunotherapy has increased the need for combination strategies. This study shows substantially higher responses with nivolumab plus ipilimumab or relatlimab than with immunotherapy alone. Larger clinical trials will be crucial to determining whether this approach should enter standard treatment protocols.