Nav: Home

Immune responses against a virus-related skin cancer suggest ways to improve immunotherapy

January 17, 2017

SEATTLE - Researchers at Seattle's Fred Hutchinson Cancer Research Center and the University of Washington say a new study suggests ways to improve immune therapy for certain cancers including a virus-associated form of Merkel cell carcinoma, a rare, aggressive skin cancer.

Merkel cell carcinoma, or MCC, is 35 times less common than melanoma, but on average, it is about three times more likely to be deadly. There are currently no therapies approved by the Food and Drug Administration for this cancer. About 80 percent of the 2,000 new cases diagnosed in the U.S. each year are caused in part by a virus - Merkel cell polyomavirus - that is often present on normal skin without consequence.

Previous studies have linked a weaker immune system with poorer survival in patients with the disease. In this study, researchers at UW and Fred Hutch, a leading center developing experimental, genetically engineered T-cell therapies, conducted an unprecedented in-depth analysis of the immune system's "killer" (CD8) T cells that respond to a specific part of the Merkel cell polyomavirus.

The immune system's effectiveness is determined by many factors, including how well T cells can infiltrate a tumor and bind to the "foreign" proteins, or antigens. More specifically, T cells seek out and attach to antigens using their highly diverse T-cell receptors. In this multicenter study, the researchers focused on T cells that target a piece of the virus referred to as "KLL".

"We found that a surprisingly low number of patients - only about 20 percent - had T cells specific for the 'KLL' region of the virus. This suggests that about 80 percent of patients aren't making T cells that recognize this very prominent target," said Dr. Paul Nghiem, affiliate investigator of the Clinical Research Division at Fred Hutch, and professor of medicine, Division of Dermatology at the University of Washington School of Medicine.

Nghiem, senior author of an article published online Jan. 16 in Cancer Immunology Research, said the study is important because an increase in the KLL-specific T cells infiltrating the tumor is associated with a striking improvement in patient survival.

First author Natalie Miller, an MD/PhD student in Nghiem's research lab, performed in-depth analysis on blood and tumors from 12 patients who had T cells that could recognize KLL.

"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," Miller said. "In addition, T cells from patients with better outcomes tended to stick to the viral target more tightly. This 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."

At diagnosis, virus-associated MCC is typically treated with surgery and radiation, and although 95 percent of patients appear to be cancer-free, the disease returns in about half of cases, Nghiem said. The cancer often responds to chemotherapy, but the response is short-lived, with most tumors progressing about three months after treatment begins.

In April, Nghiem's group published findings of a phase 2 clinical trial of the immunotherapy drug pembrolizumab, reporting that the "checkpoint inhibitor" helped to revive "exhausted" T cells, providing significant and lasting responses in more than half of patients.

With their new findings, the research team expects to propose the launch of a clinical trial in which T cells engineered with the most effective tumor tracking and attacking receptors would be transferred to patients who are unable to mount an effective immune response of their own.

"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," Nghiem said.
-end-
The study was supported by grants from the National Institutes of Health and other sources including the Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award, ARCS Fellowship, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund, and the Deutsche Forschungsgemeinschaft (SFB TR36).

Nghiem, corresponding author, is a leading expert on MCC and a pioneer of immunotherapy for the disease. His research has shed light on the importance of the immune response to Merkel cell polyomavirus. A practicing physician, he treats patients with MCC and other skin cancers at Seattle Cancer Care Alliance, Fred Hutch's clinical care partner. He is a consultant for EMD Serono Inc. and receives funding from Bristol-Myers Squibb to perform biomarker studies in MCC clinical trials.

At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch's pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer with minimal side effects. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation's first and largest cancer prevention research program, as well as the clinical coordinating center of the Women's Health Initiative and the international headquarters of the HIV Vaccine Trials Network. Private contributions are essential for enabling Fred Hutch scientists to explore novel research opportunities that lead to important medical breakthroughs. For more information visit fredhutch.org or follow Fred Hutch on Facebook, Twitter or YouTube.

FUNDING: NIH F30-CA192475-02, NIH K24-CA139052, NIH R01-CA162522-05, NIH R01-CA CA176841, NIH R01-AI094109, Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award #15CHAS04, ARCS Fellowship, Environmental Pathology/Toxicology Training Grant T32ES007032-36, NIH Center for Aids Research (CFAR) AI027757, National Cancer Institute (NCI) Cancer Target Discovery and Development (CTD2) U01 CA176270, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund, and the Deutsche Forschungsgemeinschaft (SFB TR36).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Fred Hutchinson Cancer Research Center

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...