Cancer poses scientific challenges that span disciplines—yet, too often, cancer research has been siloed and narrow in scope.
Real progress demands a different approach: one that encourages scientists to think outside the box and work together to find new ways to look at old problems. That’s why The Mark Foundation prioritizes funding multidisciplinary collaborations that elevate team science.
“Through strategic funding, we catalyze pioneering science by creating theme-based synergy,” explained Mike Carleton, PhD, senior scientific director at the Foundation.
That approach is paying off at The Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation at the University of Pennsylvania. One of three globally established Centers, the UPenn Center integrates cancer genomics, bioengineering, and computational biology to explore inflammation’s role in cancer. According to Mike, the Center is becoming a “perpetual motion research machine” where fundamental and clinical research reinforce each other, leading to breakthroughs.
Biological Riddles and Breakthroughs
The Interferon Paradox
Interferons coordinate our body’s inflammation response and play a complex role in cancer treatment. Short exposure to interferons boosts the immune system, but chronic activity can result in immune suppression and help cancer cells evade treatment, limiting the efficacy of cancer immunotherapies for many patients.
Center director Andy Minn, MD, PhD and his team are working to block cancer cells from hijacking this pathway while enhancing the body’s natural ability to combat tumors. “This paradox presents a significant challenge yet is incredibly compelling,” Andy explained.
Researchers at the Center have discovered that chronic interferon signaling can create “inflammatory memory,” enabling cancer cells to hide from the immune system. Identifying how these processes occur and how they interact with existing therapies could lead to significant steps forward in cancer treatment.
One such step was recently described by Andy and his colleagues in the June 2024 issue of Science. The UPenn team employed a seemingly counterintuitive approach—combining anti-PD1 immunotherapy, which triggers an interferon response, with a type of drug called a JAK inhibitor, known to suppress interferon responses.
In metastatic lung cancer patients who did not respond to initial anti-PD1 monotherapy, the addition of a JAK inhibitor promoted CD8 T cell plasticity and improved clinical response to anti-PD1. Understanding the mechanism(s) of JAK inhibitor enhancement of antitumor immunity and any impact on inflammatory memory are areas currently under investigation.
FLASH Radiation: A New Frontier
The Center has also made groundbreaking strides in FLASH radiation, a treatment modality that delivers several weeks’ worth of radiation in a few seconds. FLASH radiation is equally effective as traditional radiation but less toxic, possibly due to its impact on acute vs. chronic interferon induction. Understanding how FLASH radiation activates interferons could revolutionize cancer treatment by reducing treatment side effects and accelerating recovery. Constantinos Koumenis, PhD, a professor of radiation therapy at Penn, recently received an NIH grant to expand his FLASH radiation studies, illustrating the ripple effect of Mark Foundation funding.
CAR T-cell Therapy: A Collaborative Triumph
Another cornerstone of The Center’s innovation is pioneering work by Carl June, MD, to advance CAR T-cell therapies: cancer treatments in which a patient’s immune cells are engineered to recognize and attack cancer cells.
With Mark Foundation support, Carl’s team recently partnered with Constantinos to combine CAR T-cell therapy with radiation. Before they received funding from the Mark Foundation, Carl had never collaborated with Constantinos, despite the fact that they worked in neighboring labs for a decade.
“Support from The Mark Foundation helps us get people out of their own foxholes,” he said.
Cultivating Innovation and Community
The Center’s collaborative culture drives cutting-edge science at the intersection of cancer radiation therapies, inflammation, and the immune system. Its work spans research groups and institutions, and the impacts are already far-reaching.
“The Mark Foundation University of Pennsylvania Center doesn’t just enhance collaborations within Penn,” said Mike. “It’s about extending knowledge to trigger real-world applications that improve lives.”
A recent Cancer Cell publication by the MFCIIR, Memorial Sloan Kettering Cancer Center, the European Molecular Biology Laboratory, the Cancer UK Cambridge Institute, and AstraZeneca shows this ethos in action. Together, the researchers demonstrated a link between resistance-associated interferon-stimulated genes and immune cell exhaustion in non-small cell lung cancer, paving the way for novel approaches to boost anti-tumor immunity.
The Center’s achievements in just five years are remarkable—but they’re just the start. On the horizon? Projects aimed at overcoming drug resistance and preventing cancer cells from exploiting inflammation.
This story is featured in The Mark Foundation’s 2023 Annual Report. Learn more about our impact here.