03:12am Saturday 18 November 2017

Penn Team Pinpoints Immune Changes in Blood of Melanoma Patients on PD-1 Drugs That Put Potential Biomarker within Reach

NEW YORK – A simple blood test can detect early markers of “reinvigorated” T cells and track immune responses in metastatic melanoma patients after initial treatment with the anti-PD-1 drug pembrolizumab, researchers from the Abramson Cancer Center of the University of Pennsylvania report in new research being presented at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference. The new findings give more insight into how the anti-PD-1 therapy, approved last year by the U.S. Food and Drug Administration to treat metastatic melanoma, goes to work inside patients’ bodies, and potentially form the basis of a biomarker to predict which patients are most apt to respond to the immunotherapy.

Pembrolizumab, approved by the FDA for treating metastatic melanoma a year ago, is a PD-1 inhibitor, a class of drug which stimulates the immune system to attack tumors. Preclinical mouse studies have shown that in cases of metastatic melanoma, certain immune cells called CD8+ T cells have high levels of a protein called PD-1, which inhibits or prevents the CD8+ T cells from attacking the cancer. Pembrolizumab in effect, takes the brake off, helping reinvigorate the CD8+ T cells.

However, only about 40 percent of patients respond to anti-PD1 therapy, and there is currently no way to determine who will benefit from the immunotherapy. Therefore a biomarker to predict efficacy of anti-PD1 therapy is needed for early escalation of therapy in non-responders and minimizing toxicity for those who do respond, since many take the drug in combination with other therapies, like radiation and checkpoint inhibitors.

“Anti-PD-1 therapies have changed the melanoma treatment landscape, and shown impressive responses in groups of patients; however, there is still more information about its effects on the human immune system that need to be uncovered,” said the study’s lead author, Alexander Huang, MD, a clinical fellow in the division of Hematology/Oncology at Penn’s Perelman School of Medicine and Abramson Cancer Center “As a result of our study, we are encouraged to see changes suggesting reinvigoration in CD8+ T cells following treatment with pembrolizumab.”

“We are able to track clear immune changes in the blood, which means that finding a noninvasive biomarker to predict who might respond to the immunotherapy is potentially in reach,” he added.

In a phase I clinical trial, Huang and colleagues analyzed blood samples from 39 patients with metastatic melanoma over 12 weeks. For each patient, blood samples were obtained immediately before the every-three-week pembrolizumab treatment began. What’s surprising is that the majority of patients treated by anti-PD-1 therapy had a significant immune response.

The researchers focused on changes in levels of proteins characteristic of reinvigoration in CD8+ T cells positive for PD-1 (CD8+PD-1+ T cells). They found increased levels of the protein granzyme B, which is a marker of the killing capacity of a CD8+ T cell, and the protein Ki67, which is a marker of cell proliferation, in blood samples obtained after pembrolizumab treatment had started.

In addition, the frequency of CD8+ T cells positive for granzyme B was greater in blood samples obtained after pembrolizumab treatment had started compared with blood samples obtained before pembrolizumab treatment started.

“Our next step is to examine the blood-based data for each patient in context with their clinical profiles. We want to see if the magnitude of changes we found is linked to clinical response, in particular, objective measures such as tumor burden, progression-free survival and tumor shrinkage,” Huang said. “This will be crucial for determining if our data could serve as the basis of a noninvasive biomarker test for predicting which patients could be helped by pembrolizumab.”

In previous trials, pembrolizumab was shown to be twice as effective as chemotherapy, halting and occasionally shrinking tumor growth in 34 percent of patients with advanced malignant melanomas, compared to only 16 percent of patients receiving chemotherapy alone. Until recently, patients with advanced melanomas were typically told they should not expect to live for more than six to nine months. But in one trial, 60 percent of patients who received pembrolizumab survived for at least 12 months. The drug is so new that longer-term survival data do not yet exist.

Dr. Huang is mentored by E. John Wherry, PhD, director of the Institute For Immunology at Penn, and Tara Gangadhar, MD, an assistant professor of Hematology/Oncology. The team also includes Lynn Schuchter, MD, chief of the division of Hematology/Oncology and Ravi Amaravadi, MD, an associate professor of Hematology/Oncology.

This study was supported by funds from the National Institutes of Health and Merck, manufacturer of pembrolizumab. Huang has no affiliation with Merck.

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.


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