A researcher at MUSC Hollings Cancer Center is advancing the next generation of cancer treatment with the support of two grants from the National Institutes of Health (NIH). The NIH's National Cancer Institute is funding these innovative projects to develop immunotherapies that strengthen the immune system in its fight against cancer.
Both projects center on T-cell therapies that use a patient's own immune system to target and destroy cancer. T-cells are immune cells that act as the body's natural defenders, playing a critical role in finding and destroying infected or abnormal cells.
They are led by Shikhar Mehrotra, Ph.D., co-scientific director of the Center for Cellular Therapy and co-leader of the Cancer Biology and Immunology Program at Hollings. Mehrotra's lab is committed to understanding T-cell biology to improve immunotherapies for cancer. Hollings researcher Paramita Chakraborty, Ph.D., will also be instrumental in leading both projects.
"The aim is to engineer T-cells that can better recognize and kill tumors and thereby improve our body's ability to defend against and fight off cancer," he said.
A focus on T-cells
A common thread between Mehrotra's funded projects is a focus on T-cells. But the projects apply different approaches to attack cancer on two fronts:
Project 1 – Enhance the immune system to make T-cells more effective.
Project 2 – Remove protections on tumors to make it easier for T-cells to do their job.
T-cells play a critical role in maintaining health. But when cancer grows in the body, it creates a hostile environment around it that blocks the immune system and makes it difficult for T-cells to function.
"The tumor microenvironment is incredibly harsh," Mehrotra said. "Our goal is to engineer T-cells that can survive those conditions. At the same time, we want to destroy other cells that help tumors hide from the immune system."
Training T-cells to thrive under pressure
Mehrotra's first project builds on a way his lab has found to make T-cells stronger: Stress them out. Mehrotra's team is testing whether a small amount of stress – in the form of carbon monoxide gas – can improve how T-cells fight cancer. Could a little bit of stress help supercharge these cancer-fighting immune cells?
While it might seem counterintuitive that being stressed would strengthen T-cells, it makes sense in the context of the tumor environment, which is low in nutrients and oxygen and high in stress. These harsh conditions can cause T-cells to get worn out and stop working. To combat that, Mehrotra's lab exposes T-cells to small, controlled amounts of stress in the lab, which activates internal repair processes that make the cells stronger and more resilient.
"This temporary stress kickstarts protective processes inside the cells, forcing them to fire up their defenses," Mehrotra said. "We want to train T-cells' energy systems (mitochondria) to work harder and survive longer in nutrient-poor, oxygen-deprived tumor environments, allowing them to do what they do best – destroy cancer cells."
"We want to give patients the best cells possible – ones that are built to last. Just a few hours of stress give the cells a push. They activate repair machinery, and when the carbon monoxide gas is gone, some retain a more resilient, functional state."
Shikhar Mehrotra, Ph.D.
After exposing T-cells to the stressor and measuring their responses, Mehrotra's team can identify and select the strongest ones and use only those in therapies.
"We want to give patients the best cells possible – ones that are built to last," Mehrotra explained. "Just a few hours of stress give the cells a push. They activate repair machinery, and when the carbon monoxide gas is gone, some retain a more resilient, functional state."
The strategy has already been successful in preclinical models. T-cells performed better and lasted longer after being briefly exposed to carbon monoxide. Clinical trials are now in the works, and the team has submitted a patent on the method.
Breaking down cancer's defense system
But making T-cells stronger may not be enough: Cancer tumors do not just sit quietly – they actively fight back. One way they do so is by recruiting myeloid-derived suppressor cells that block the body's natural immune response. Instead of helping the body fight disease, these cells protect tumors by preventing T-cells from working properly, making them a major obstacle in cancer treatment.
Mehrotra's second project focuses on modifying the cancer environment by weakening these tumor "bodyguards." The goal is to reduce their ability to support tumor growth.
"In the first project, we're trying to make T-cells stronger. In this one, we want to make the suppressive cells dysfunctional, so they don't stop good T-cells from mounting a defense."
His lab discovered that myeloid-derived suppressor cells rely on a fat-based molecule to do their job. Using a drug originally developed at MUSC, they were able to block this molecule and disrupt the suppressor cells. Disabling the cells then cleared the way for T-cells to come in and fight the tumor more effectively.
That drug has already been tested safely in patients with cancer. The researchers are now looking to combine it with immune-based treatments in clinical trials for cancers where myeloid-derived suppressor cells are common, like breast, colon and brain cancers.
A long-term investment in discovery
Mehrotra's projects are part of a broader push at Hollings to develop cutting-edge cellular therapies that translate lab discoveries into real-world treatments for cancer patients. These newly funded projects are a major step toward that goal of improved treatment for many cancers, particularly those that have immune suppression as a major hurdle.
"T-cells are like smart drugs – engineered to recognize only the tumor. You inject them once, and they continue doing their job. That's why cellular therapy is the next frontier," Mehrotra said.
Importantly, these immunotherapies often have fewer side effects than traditional treatments and can be personalized or packaged as off-the-shelf options.
Mehrotra was quick to emphasize the broad collaborative effort that happens behind the scenes to enable these sorts of advances.
"This kind of work takes time. It takes effort. And it takes collaboration. But the goal is to bring something new to patients, especially if they haven't responded to existing treatments. That's what drives us – giving hope to patients who have run out of options."
Both projects also build on more than a decade of foundational research funded by NIH. Mehrotra pointed to the importance of federal funding to sustain this type of cutting-edge research and move it from basic science to clinical translation.
"Without NIH's support, this kind of long-term, high-risk research just wouldn't happen," he emphasized. "The funding enables labs like mine to pursue innovative ideas and conduct comprehensive studies that may take years to come to fruition, ensuring that promising research can progress toward clinical applications."
As Hollings continues to expand its cellular therapy program, these projects represent an important step toward more personalized, effective and lasting treatments for cancer.
