Immune checkpoint inhibitors (ICI) are a promising form of cancer immunotherapy, treating cancer by activating the patient’s own immune system. While patients whose cancer responds to ICI treatment experience excellent results, a large percentage of patients fail to respond to the therapy. One of the causes of poor response is due to the presence of certain immune cells within the tumor that lead to elevated levels of adenosine, a compound found naturally in cells that causes immune suppression when present in high levels.

In the new study, the UofL researchers have enhanced the response to ICI therapy by combining it with PEGylated adenosine deaminase, a drug already approved by the FDA that reduces levels of adenosine. The study, led by Kavitha Yaddanapudi, associate professor in the Division of Immunotherapy, the Hiram C. Polk, Jr., MD Department of Surgery and researcher with the UofL Health – Brown Cancer Center, was published June 30 in . ��

Using lung, melanoma and breast cancer animal models and patient cell samples from the Brown Cancer Center biorepository, the team showed that when PEGylated adenosine deaminase is used in combination with ICI therapy, cancer-fighting T cells become more active, thereby attacking the tumor.

“This is a very exciting discovery. We found one particular mechanism by which the adenosine levels were going up in the tumors and what we can do to mitigate it,” Yaddanapudi said. “And when we combine this drug with immune checkpoint inhibitor therapy, we get a very nice synergistic effect in the tumor control.”

PEGylated adenosine deaminase is FDA approved for lifelong use in children with immunodeficiency to increase their immune function.

“This is a drug that has been FDA approved for use in kids for a different disease and now we are repurposing it for cancer, so we hope it can quickly go into the clinic to confirm its ability to enhance immunotherapy in patients,” Yaddanapudi said.

“If it turns out to be an effective drug, it subverts both a natural defense mechanism against inflammation (elevated adenosine) and is an already approved agent (by the FDA),” said John Eaton, professor emeritus in UofL’s Departments of Medicine and Pharmacology & Toxicology and study team member and co-author.

The discovery has the potential to further reduce deaths from cancer, according to Jason Chesney, director of the UofL Health – Brown Cancer Center.

“ICIs have markedly improved the long-term survival of certain cancer patients and have reduced cancer death rates across the world,” Chesney said. “Many cancer patients do not respond to ICIs, but Dr. Yaddanapudi’s exciting discovery opens the door for human trials combining ICIs with PEGylated adenosine deaminase to overcome this resistance.”

Seven projects were selected, two of which are from UofL:

• A novel immunotherapeutic compound for uveitis, an inflammatory disorder of the eye that ranks as the fifth most common cause of blindness. Development is led by Howard Donninger and Kavitha Yaddanapudi, both of medicine; and Hui Shao, of ophthalmology and visual sciences.
• A point-of-care acute clinical differential scanning calorimetry��(DSC) device for the real-time diagnosis and classification of heart attacks. Development is led by Tommy Roussel, of mechanical engineering; Nichola Garbett, of medicine; and Andrew DeFilippis.

KYNETIC is a statewide program supported by $6.6M in funding, including a $4M�� Research Evaluation and Commercialization Hub (REACH) grant from the National Institutes of Health and matching funds. The goal is to advance the most promising biomedical research innovations — including pharmaceuticals, therapies and devices — from the state’s eight public universities and the Kentucky Community & Technical College System.

Applications require a two-page pre-proposal and are for the next cycle of KYNETIC funding. Funding cycles are offered twice a year and are open to faculty, staff, trainees and students.��Competitive renewal opportunities are available.��

Launched in 2019, the KYNETIC program builds on UofL’s strong history of translational research support, which includes a previous NIH REACH program (“UofL-ExCITE”) and a prestigious suite of programs funded by the National Science Foundation and Wallace H. Coulter Foundation. Paula Bates, professor of medicine at UofL, who co-leads KYNETIC, said the idea is to spur innovation and economic development through shared knowledge and ideas.

“Innovation is, in many ways, about collaboration,” she said. “It’s probably not a coincidence that most of our successful projects involve multidisciplinary teams because that’s a great catalyst for innovation. And KYNETIC is all about working together … sharing what we’ve learned and learning from other people. It’s a really powerful way to reach everybody in Kentucky and use our collective expertise to help to turn great ideas from our state into products that improve people’s health and wellbeing.”

KYNETIC is led by UofL, the University of Kentucky, and the Kentucky Cabinet for Economic Development, and works closely with Kentucky’s regional universities and colleges, as well as with Kentucky Commercialization Ventures.