Nav: Home

Penn team pinpoints immune changes in blood of melanoma patients on PD-1 drugs

September 16, 2015

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.
-end-
Dr. Huang is mentored by . 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.

University of Pennsylvania School of Medicine

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
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.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.