Potential Reason Behind Failed Immunotherapy for Melanoma

Researchers evaluate mechanism that prevents immune system from attacking tumors in melanoma.

Findings from a recent study suggest that patients who do not respond to immunotherapy using tumor-infiltrating lymphocytes carry mechanisms that switch genes on or off in those cells.

Researchers discovered what they call “gene dysregulation,” which makes T cells revert back to an immature state in certain patients with metastatic melanoma. The findings of the study were presented at the 2016 American Society of Clinical Oncology Annual Meeting.

"Our research offers key evidence for genetic and epigenetic dysregulation as a reason these powerful immune therapies fail to work for so many people with widespread melanoma," said study senior investigator Jeffrey Weber, MD, PhD.

Immunotherapies fail in part from tumor cells that suppress T cell populations necessary for the treatment to be successful. Researchers included 24 patients with melanoma and analyzed patterns of changes in the epigenome to search for epigenetic changes that would account for the lack of response to immunotherapy and the reasons behind these changes.

Researchers discovered more than 60 epigenetic changes and 10 changes in gene activity common among the patients. A majority of the changes were known to control whether immature cells become CD4 or CD8 T cells, according to the study.

Since both types of cells are important for immunotherapy, researchers believe these changes could potentially cause T cell malfunction. The researchers said they plan to conduct additional epigenetic analyses in patients with advanced melanoma.

"If our research is confirmed, it suggests that by modifying the genetic or epigenetic alterations we have identified, we can potentially turn treatment non-responders into responders and broaden the success that immunotherapies are having against melanoma and other cancers," said study lead investigator David Woods, PhD.

These corrective actions could potentially be corrected in patients’ T cells in a lab and then injected back into the patient, according to the study.

Reprogramming dysfunctional T cells could potentially make immunotherapy more effective, especially in conjunction with immune-boosting agents, such as interleukin-2 or checkpoint inhibitors, the study concluded.