Tumour-infiltrating Merkel cell polyomavirus-specific T-cells associated with improved patient survi
Photo credit: Fred Hutch News Service
Intratumoural infiltration by Merkel cell polyomavirus (MCPyV) specific T-cells has been associated with significantly improved Merkel cell carcinoma (MCC) survival. That suggests augmenting the number or avidity of virus-specific T-cells may have therapeutic benefit, according to findings published in Cancer Immunology (Jan. 16, 2017; 5(2):1–11).
In this study, investigators from the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle analyzed the immune system’s “killer” (CD8) T-cells in response to the Merkel cell polyomavirus. The focus was a specific piece of the virus known as “KLL,” which was targeted by the T-cells.
During this multicenter study, the researchers performed in-depth analysis on blood and tumours from 12 patients with T-cells that could recognize KLL.
This investigation is important because an increase in the KLL-specific T-cells infiltrating the tumour is associated with striking improvement in patient survival, said Natalie Miller, the first author of the study.
“We found that a surprisingly low number of patients—only about 20 per cent—had T-cells specific for the ‘KLL’ region of the virus. This suggests that about 80 per cent of patients aren’t making T-cells that recognize this very prominent target,” says Dr. Paul Nghiem, investigator of the Clinical Research Division at the Fred Hutchinson Cancer Center, and professor in the Division of Dermatology at the University of Washington School of Medicine.
“T-cells that recognize this part of the virus are incredibly diverse. In fact, among these 12 patients, there were 397 unique ways for the T-cells to recognize this single short piece of the virus; only one T-cell receptor was shared between two patients,” said Miller, a MD/PhD candidate in Dr. Nghiem’s lab at the University of Washington, who was quoted in a press release.
The findings, according to Miller, indicate that T-cells from patients with better outcomes tended to stick to the viral target more tightly. She added that this outcome “suggests that while nature has created many ways for the immune system to fight this cancer, some ways are better than others. Our hope is that these better T-cell receptors can be turned into a therapy for patients who do not have them.”
Current treatments for virus associated MCC involves surgery and radiation. About 95% of the patients seem to be cancer-free after undergoing these treatment methods, but as seen in half the cases, the disease returns, said Dr. Nghiem.
Dr. Nghiem and his team have recently published findings of a phase 2 clinical trial drug known as pembrolizumab. The “checkpoint inhibitor” of this immunotherapy drug has demonstrated that it can revitalize “exhausted” T-cells, showing important and long-lasting effects in more than half the patients.
These new findings will help the research team propose and launch a clinical trial that involves genetically engineered T-cells that could be transferred into patients with a weak immune response. This T-cell therapy method will be tailored to effectively target tumors and attack receptors in patients with virus-associated cancers such as MCC.
“Like Merkel cell carcinoma, cancers that have a viral component provide a variety of potential targets for immunotherapy. We’re eager to find out if transgenic T-cell therapy can ‘reprogram’ lymphocytes to eliminate tumors in combination with checkpoint inhibition,” concluded Dr. Nghiem.