New research from multiple institutions has identified a correlation between the presence of bacteria within tumors and patient response to immunotherapy for head and neck squamous cell carcinoma. Studies published in Nature Cancer suggest that elevated bacterial levels in the tumor microenvironment can suppress the immune system, potentially leading to immunotherapy resistance. These findings emerged from investigations, including analyses of data from the JAVELIN Head and Neck 100 Phase III clinical trial, and propose that modulating tumor bacteria could enhance treatment effectiveness.
Discovery of Bacterial Influence
Researchers from Memorial Sloan Kettering Cancer Center (MSK) and Cleveland Clinic, among others, found that tumors with higher bacterial loads tend to attract myeloid cells, specifically neutrophils. These myeloid cells are observed to suppress the immune response, which counteracts the intended effects of immunotherapy. Conversely, patients whose tumors exhibited higher levels of T cells and lower levels of bacteria and myeloid cells were more likely to respond favorably to immunotherapy. The research indicates that the overall bacterial load, rather than specific bacterial strains, is associated with this effect.
JAVELIN Head and Neck 100 Trial Analysis
A significant part of this research involved the analysis of the JAVELIN Head and Neck 100 clinical trial. This international multicenter Phase III trial explored the checkpoint inhibitor avelumab (Bavencio®) in combination with standard chemoradiotherapy for patients with squamous cell carcinoma of the head and neck. The trial did not yield anticipated results for a majority of participants. Subsequent analysis revealed that patients with high tumor bacteria levels experienced less favorable outcomes when treated with the immunotherapy combination compared to those receiving standard chemoradiotherapy alone.
Investigators, including MSK radiation oncologists Dr. Nancy Lee and Dr. Nadeem Riaz, and Cleveland Clinic's Dr. Timothy Chan, Dr. Daniel McGrail, and Dr. Natalie Silver, validated these findings through patient samples, preclinical models, and clinical trial data. Dr. Silver's preclinical models demonstrated that administering antibiotics reduced tumor size and improved immune response, while introducing bacteria rendered tumors resistant to immunotherapy.
Proposed Mechanism and Future Directions
The collective findings suggest a mechanism where elevated bacterial levels in tumors attract neutrophils. While neutrophils are crucial for fighting bacterial infections, their presence in the tumor microenvironment may suppress the immune system's required function for effective immunotherapy, particularly by impairing T cell activity.
Building on these discoveries, researchers plan further investigations and clinical trials:
- A clinical trial is scheduled for 2026 to assess the impact of antibiotics on tumor bacteria and the microenvironment in head and neck cancer patients prior to surgery. This trial will involve biopsies before antibiotic administration and post-surgical analysis of removed tumors.
- Dr. Silver has initiated a separate clinical trial, funded by the American Cancer Society and VeloSano, to assess whether antibiotics can reduce tumor microbiome levels and enhance immunotherapy response in head and neck squamous cell carcinoma patients.
- Dr. McGrail is conducting research on how bacteria influence cancer development and the factors leading to higher bacterial presence in certain tumors, aiming to develop new therapeutic strategies.
- Dr. Chan is investigating the potential for bacteria to induce DNA mutations within tumors.
These efforts aim to develop interventions, such as incorporating antibiotics into treatment protocols, to modulate bacterial presence within tumors and potentially enhance immunotherapy effectiveness for patients who might otherwise not respond.
Contributing Institutions and Funding
The research was led by investigators from institutions including Memorial Sloan Kettering Cancer Center and Cleveland Clinic, with collaboration from others such as Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. Dr. Nancy Lee serves as MSK's Service Chief of Head & Neck Radiation Oncology, and Dr. Nadeem Riaz is Associate Director, Genomics Operations, Immunogenomics and Precision Oncology Platform at MSK. Dr. Timothy Chan is chair of Cleveland Clinic's Department of Cancer Sciences.
Funding for the study was provided in part by NIH/NCI Cancer Center Support Grant P30 CA008748. The JAVELIN trial was sponsored by Pfizer and conducted under an alliance between Merck and Pfizer. Dr. Riaz disclosed research support from Pfizer, REPARE Therapeutics, Invitae, and Bristol-Meyers. Dr. Silver's clinical trial is funded by the American Cancer Society and VeloSano.
The findings were published in Nature Cancer on January 2, 2026.