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