Preventing exhaustion in immune cells boosts immunotherapy in mice

PITTSBURGH, March 6, 2018 – If you're an immune cell gearing up to fight cancer, you'd better eat your breakfast. The tumor microenvironment is a harsh place, and tumor cells are ready to wear you out.

Cancer immunotherapies that improve the ability of T-cells – highly specialized immune soldiers – to attack cancer have made major strides in the clinic. However, they work only for 10 to 30 percent of cancer patients. One reason for this is a phenomenon called "T-cell exhaustion," where the T-cells that are most specialized to kill cancer are continually stimulated, becoming drained of their energy due to the harsh conditions inside the tumor. New research from the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center shows that preventing or reversing this metabolic exhaustion with targeted therapies could enhance the effects of immunotherapy, potentially allowing them to help more patients.

The research, published today in the Journal of Experimental Medicine, reveals this insight by uncovering how a protein on the surface of T-cells, called 41BB, works. 41BB is part of a family of "co-stimulators" normally activated when T-cells are fighting infections, but the conditions inside a tumor prevent this from occurring. Previous research has shown that activating 41BB helps T-cells replicate and persist long-term, but how it does that has remained a mystery.

"What we found is that 41BB's effect can be almost completely chalked up to how it alters T-cell metabolism. In a sense, activating 41BB keeps the T-cells well fed so they last longer in a fight," said Greg M. Delgoffe, Ph.D., assistant professor of immunology at Pitt's School of Medicine and an investigator at the UPMC Immune Transplant and Therapy Center.

In lab-grown mouse T-cells, the researchers found that a protein antibody that activated 41BB caused its mitochondria – the cellular powerhouses – to both grow in number and fuse with each other.

"Activating 41BB increased the energy reserves of T-cells so they were ready to swiftly unleash their killing ability on demand," said Ashley Menk, a researcher in Delgoffe's lab and the first author of the study.

However, drugs that activate 41BB have not had much success on their own in clinical trials. To overcome this, the researchers tested whether 41BB activation, while not effective on its own, could improve the effect of two immunotherapy approaches: a checkpoint inhibitor drug that blocks the PD1 protein on T-cells and a cellular therapy that uses engineered T cells to recognize tumor cells.

When tested in a mouse model of melanoma that normally responds poorly to PD1 immunotherapy or therapeutic T cells on their own, the combination resulted in much better outcomes.

"While activating 41BB fixes the fuel issue, it doesn't appear to fix the immunological issue, which is what checkpoint inhibitors or cellular therapies are great at. The combination of the two, we found, was better than the sum of its parts," said Delgoffe.

Intriguingly, the team also found that pre-treating mice with a short duration of 41BB activation followed by PD1 immunotherapy was as good as using both drugs throughout, an approach that could potentially avoid side effects associated with long-term 41BB activation.

The researchers are testing the combination treatment in human tumor models and expect to conduct clinical trials in the near future.

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Additional authors on the study are Nicole E. Scharping, Dayana B. Rivadeneira, Ph.D., Michael J. Calderon, McLane J. Watson, Deanna Dunstane and Simon C. Watkins, Ph.D.

The study was supported by Sidney Kimmel Foundation for Cancer Research grant SKF-015-036, Stand Up To Cancer-American Association for Cancer Research grant SU2C-AACR-IRG-04-16, and National Institutes of Health grants DP2AI136598, T32CA082084, F99CA222711 and P30CA047904.

About the University of Pittsburgh School of Medicine

As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.

Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.

UPMC Hillman Cancer Center, the region's only National Cancer Institute-designated Comprehensive Cancer Center, is one of the largest integrated community cancer networks in the United States. Backed by the collective strength of UPMC and the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center has more than 60 locations throughout Pennsylvania, Ohio, Maryland and New York, with seven international cancer centers and partnerships. Consistently ranked by U.S. News & World Report for excellence in cancer care, the more than 2,000 physicians, researchers and staff are leaders in molecular and cellular cancer biology, cancer immunology, cancer virology, biobehavioral oncology, and cancer epidemiology, prevention, and therapeutics. UPMC Hillman Cancer Center is transforming cancer research, care, and prevention — one patient at a time.

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http://dx.doi.org/10.1084/jem.20171068

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