Study identifies predictors of immunotherapy response in head and neck cancer
Dana-Farber Cancer Institute scientists say they have identified factors that predict improved response and survival in patients with head and neck cancers treated with checkpoint inhibitor immunotherapy.
Two immunotherapy agents known as checkpoint inhibitors have been approved to treat patients whose disease is resistant to standard platinum-based chemotherapy. However, only a minority of such patients respond to these agents, and there are no reliable markers for predicting which patients will benefit.
An estimated 13 to 18 percent of platinum-resistant head and neck cancer patients have responses — tumor shrinkage — to the checkpoint inhibitors pembrolizumab or nivolumab, says Glenn J. Hanna, MD, an oncologist in Dana-Farber's Head and Neck Cancer Center and first author of the report in the journal JCI Insight.
Previous studies have suggested that patients whose head and neck cancer is driven by infection with the human papillomavirus, HPV, or whose tumors have a significant level of the PD-L1 checkpoint protein are somewhat more likely to respond, Hanna says, but these factors are not routinely used to guide treatment decisions. In practice, "we give everyone a chance" with the checkpoint inhibitors, he says.
In search of additional predictive biomarkers, Hanna and his colleagues studied a group of 126 patients with squamous cell carcinoma of the head and neck (SCCHN) who had been treated with drugs inhibiting the PD-1 or PD-L1 checkpoints. These checkpoints are molecules on T cells and tumor cells that form a system used by cancer cells to suppress the patient's immune response against tumors. Checkpoint inhibitors like pembrolizumab and nivolumab release the checkpoint brakes and free the immune system's T cells to attack the cancer.
Among the 126 patients in the study, the investigators observed six (5 percent) complete responses, meaning that the cancer became undetectable. There were 11 (9 percent) partial responses, meaning the tumors decreased in size. The researchers used several types of analyses to look for factors associated with better or worse response.
As had been suggested in earlier reports, patients positive for HPV had increased survival. Another finding, which was somewhat surprising, was that patients who had received chemotherapy prior to immunotherapy had significantly longer survival — 10 months vs. 3 months — than individuals who had received only surgery and/or radiation therapy prior to the immunotherapy drugs. Hanna says this observation could guide choices of when to give chemotherapy in relation to immunotherapy for head and neck cancers.
Among patients whose cancers were not caused by the HPV virus, the researchers discovered that head and neck tumors exhibiting higher total mutational burden (TMB) — the number of DNA alterations in the tumor's genome — were more likely to respond to checkpoint inhibitor drugs. The probable explanation is that cancer cells with many DNA mutations produce a large number of "neoantigens" – cancer-specific proteins that make the tumor more easily recognized by the patient's immune system.
Virus-negative patients who responded to immunotherapy, the study revealed, were more likely to have a type of DNA change called frameshift mutations in tumor-suppressor genes, as well as mutations in the genes NOTCH1 and SMARCA4. The responders' tumors also were more likely to have been infiltrated by immune CD8-positive T cells — a sign that the patient's immune system had already mounted a response against the presence of the cancer cells.
"While further validation is warranted," the authors write, "these observations provide potentially novel insights regarding the genomic determinants of immunotherapy response in SCCHN."
Hanna says the findings, while preliminary, could begin to influence decisions around treating patients. "If a given patient's tumor genomic data show that they carry these mutations or have high mutational burden, it may support using a PD-1/L1 inhibitor earlier in their treatment," he says.
The senior authors of the report are Laura E. MacConaill, PhD, scientific director of Profile, and Robert I. Haddad, MD, disease center leader of the Center for Head & Neck Oncology.