ECU and ECU Health researchers explore behaviors in melanoma immune cells

A researcher in the Brody School of Medicine has joined forces with a Brody/ECU Health surgical oncologist on a two-year, $200,000 Department of Defense Melanoma Research Program funded project that aims to better understand why some melanoma patients respond to immune therapies while others do not.

Dr. Nasreen Vohra, an associate professor in Brody’s Department of Surgery and a surgical oncologist with ECU Health, is teaming up with Dr. Kelsey Fisher-Wellman, an assistant professor in Brody’s Department of Physiology, on a melanoma discovery project that could lead to a better understanding of how the “powerhouse” of  immune cells, called mitochondria, differ in melanoma patients; because how a cell utilizes energy is fundamentally linked to how well it works, this information could eventually open doors to new treatments.

This project involves using biopsies of melanoma tumors and immune cells from blood and lymph nodes of patients treated at ECU Health. Vohra and Fisher-Wellman want to better understand how immune cell dysfunction specifically related to how it uses energy keeps immune therapies from working against melanoma, the deadliest type of skin cancer.

In addition to surgery, melanoma treatment often includes immune therapy — a type of cancer treatment that helps the immune system fight cancer.

“Although immune therapy has improved patient outcomes, a significant proportion do not respond,” Vohra said. “While we have made great strides with melanoma and immunotherapy, about 50% of patients will not respond to immunotherapy, especially in this region, where we have patients who have acral lentiginous melanomas (skin cancer that appears on the palms of the hands, the soles of the feet or under the nails; also more common in darker skin individuals) are not as responsive to immunotherapy.”

The study will take a closer look at the mitochondria of T-cells — an important type of white blood cell that plays a central role in immune response — and how dysfunctions in some cells could inhibit treatment success.

“Given our overlapping expertise in mitochondrial biology — Dr. Fisher-Wellman — and my expertise in T-cell immunity and immunotherapy, our unique ‘bioenergetics to bedside’ approach is poised to discover the fundamental bioenergetics (how cells use energy to perform their respective functions) that drive melanoma T-cell failure,” Vohra said. “Results from this work are intended to fill the critical first step in developing novel mitochondrial diagnostics and targeted therapies.”

Vohra’s patient care experience and Fisher-Wellman’s lab research expertise yield a unique pairing that offers a panoramic approach to the study.

“Having a diverse perspective is very important in solving a problem,” Vohra said. “If you are a physician, you certainly have the perspective of seeing the patient and knowing how they do when you treat them and the barriers you encounter. If you’re a researcher, you’re focused on a specific problem at the bench. We can all get tunnel visioned in our respective fields, so it’s very important to get a perspective outside your area of expertise because that greatly increases the likelihood of solving the problem.”

Dr. Nasreen Vohra

Dr. Nasreen Vohra is a surgical oncologist with ECU Health and has been with the Brody School of Medicine’s Department of Surgery for a decade.

According to the Centers for Disease Control, more than 88,000 new cases of melanoma were reported in 2019 in the United States; more than 8,000 of those were fatal.

The Department of Defense grant will underscore that each of those numbers is a patient with a story — and that each patient’s melanoma could react differently to treatment.

Audrey Taylor travels from Ivanhoe to see Vohra since a stage 3 melanoma diagnosis nearly two years ago. His case is complex because the cancer spread to his liver soon after his initial diagnosis despite being on immunotherapy. He enrolled in a clinical trial initially and has also elected to participate in this study to help his doctor learn more about his disease and how best to treat stubborn cases.

“Since I got to know her, I knew that she was going to take care of me to whatever length I needed to go to,” Taylor said. “That’s what made me feel so secure about coming, because I still think about all those treatments, going on two years now, and I never missed a day because I know that if I do my part, they already did their part by offering this service.”

Vohra calls Taylor a “model patient who has continued to contribute to overall knowledge not only on melanoma” but also broadly to the field of immunotherapy.

“I just know we aren’t done yet,” Taylor said. “I’ll be honest with you: This has been an amazing journey for me. I’d never been to the hospital; I’d never been sick. That just goes to show that you don’t know what’s down this road. Whatever I have to do, I’m willing to do it 100%. If it helps one person, it’s been advanced.”

Patients and volunteers like Taylor could help provide insight on how T-cells in tumors use energy and why some of them don’t function properly.

“It’s been known for a really long time that solid tumors have T-cells in them,” Fisher-Wellman said. “So why are the T-cells not killing the tumor? That’s kind of the basis for immunotherapy; if you can turn those T-cells back on, they already know where the tumor is and they could potentially clear it. So, what we’re doing is taking melanoma samples from the clinic, culturing out the T-cells and asking if there are disruptions in the mitochondria of those T-cells that might explain why they are not fighting the cancer.

“This phase of the grant is to really rigorously profile what the mitochondria look like in the tumors,” he added. “We’re coming at it from a functional lens; we’re just looking to see if there are functional differences.”

Vohra added that the study will have two phases.

“Our first project is to develop foundational information where we look at T-cells in healthy volunteers and in melanoma patients — these are untreated patients, patients who have not seen any treatment — and we want to take a look at the immune cells in their tumor and the immune cells in their lymph nodes and see how their metabolic profiles differ based on what kind of T-cell it is,” she said.

The second phase will get more specific.

“We’re going to take not only cells from untreated patients, but also patients who have received some immunotherapy,” Vohra said. “With this approach, because we know some patients will respond and some patients unfortunately won’t, we will have a good mixture of patients who are responding to immunotherapy and don’t have disease and some who are not. It will give us an opportunity to look at their outcome and correlate it to their T-cell function.”

The study will also allow researchers to work with samples from a diverse patient and volunteer base, Vohra added, that reflects the demographics of eastern North Carolina.

Fisher-Wellman said the project is a chance to reveal some of the mysteries of cell behavior and how it impacts disease.

“That’s what I love about discovery science: You don’t know what you’re going to find, and you follow up and generate your hypotheses. There’s something very gratifying about that,” he said. “We’re very excited; this is a very important grant for us. We’ll have this wealth of experience that we can tap into. There’s all that opportunity for intervention if you understand it — and we’re trying to understand it.”