That work will continue and expand at UofL thanks to $11.5 million in new funding from the National Institutes of Health. The funding will support continuing research in the CCII to investigate therapies that activate the immune system against cancer and to train the next generation of cancer researchers and oncologists.

Since its launch, the CCII has helped four young researchers obtain independent federal funding and doubled the immune-oncology faculty at UofL from 10 to 20 members. The center’s faculty and research facilities also support highly successful clinical trial program.

“The power and impact of our clinical and translational research in cancer immunotherapy are undeniable. This work provides hope for people facing a cancer diagnosis,” said UofL President Gerry Bradley. “I am grateful to our researchers and clinicians who devote their careers to advancing innovative therapies that benefit cancer patients in Kentucky and beyond and I am excited to see what the next phase brings.”   

The CCII was created with an initial five-year Center of Biomedical Research Excellence (CoBRE) grant of $11.5 million in 2020. The new $11.5 million CoBRE grant announced today will support the center’s work for an additional five years.

An essential component of the CCII’s mission is translating research into the clinical realm, making UofL Health an essential part of its work. CCII supports and is supported by Brown Cancer Center.

“UofL Health – Brown Cancer Center has been developing novel immunotherapies since the early 2000s and our collaboration with UofL’s research and educational programs has translated into lives saved not only in our region but also throughout the country,” said Jason Smith, chief executive officer of UofL Health. “This grant highlights the advantage of academic health care. We are able to leverage life-changing research from the University of Louisville and elsewhere, and put it to work to save and improve the lives of our patients.”

UofL and UofL Health – Brown Cancer Center are leaders in translating scientific discoveries to patient care and conducting clinical trials that bring new therapies to patients and improve chances of recovery for patients. Brown Cancer Center has led multiple clinical trials of tumor-infiltrating lymphocytes (TILs) therapy, and in 2024, the cellular therapy was for metastatic melanoma.

“The UofL Health – Brown Cancer Center has been a leader and innovator when it comes to novel therapies like TILs,” said Jason Chesney, director of Brown Cancer Center and . “We started offering TILs in clinical trials back in 2016. We have seen many patients who were told elsewhere that they had no other options, but they’ve come to us, and their lives have been extended for years. This grant has allowed us to continue this research so more of our patients can make it to weddings, graduations and meet their grandchildren.”

Julie Reynolds, 69, was the first patient treated with commercial TILs for metastatic melanoma after its FDA approval in February 2024. The retired teacher and Indiana resident was treated at Brown Cancer Center with TILs therapy in June 2024 and is alive and well today.

“The clinical trials of TILs that were conducted by Dr. Chesney at UofL Health – Brown Cancer Center led to the FDA approval of TILs last year which in turn led to me being alive so that I can enjoy spending more time with my family,” Reynolds said.

Training the next generation of investigators

One key goal of CoBRE programs is to train talented young investigators to become the next generation of research leaders. At CCII, young investigators benefit from project grants and mentoring by senior investigators, supported by CoBRE funding. All four of the young investigators who led projects under the first round of center funding have now obtained major federal funding of their own, including:

• Chuanlin Ding
• Qingsheng Li
• Corey Watson
• Kavitha Yaddanapudi

“When we launched this center, our mission was ambitious: to build a vibrant community of scientists who could bridge fundamental immunology with translational and clinical research, ultimately bringing new hope to patients with cancer,” said Jun Yan, director of the CCII. “Through this next phase, we will continue to provide a nurturing environment where junior investigators can develop cutting-edge research programs, gain access to advanced technologies and receive the mentorship and resources they need to succeed.”

As a first-round project leader in the program, Yaddanapudi’s translational research supported the clinical immunotherapy program at Brown Cancer Center. She investigated immune checkpoint inhibitor resistance in lung cancer patients to improve treatment and worked with the TILs clinical trial team. Now, Yaddanapudi is a mentor for other young investigators in CCII as they build their research programs.

Junior investigators currently receiving support and training include:

• Sharmila Nair
• Jian Zheng
• Joseph Chen

The center also houses research instruments in its Functional Immunomics Core facility. The equipment supports research by the CCII faculty, the junior researchers and other investigators at the university. It houses a Helios CyTOF instrument and a Hyperion Imaging Mass Cytometry, among other resources. To date, investigators within the program have secured approximately $33 million in research grants made possible by the core.

As part of its next phase, the CCII plans to add a tumor organoid fragment culture platform. The platform uses human tumor specimens and mimics the human body environment for more precise testing.

View photos from the announcement on .

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

“At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died,” said Jiapeng Huang, anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine.

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in .

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

This research is supported by the National Heart, Lung, And Blood Institute under award numbers R01HL158779 and R43HL169129 and the National Institute of Allergy and Infectious Diseases under award number R01AI172873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

University of Louisville researchers recently have shown that beta-glucan, a natural carbohydrate, can generate enhanced immune responses to cancer in the pancreas and may lead to improved efficacy of immunotherapy for pancreatic cancer.

Jun Yan, chief of the Division of Immunotherapy in the Department of Surgery at UofL, said one of challenges for pancreatic cancer is that natural immune cells are unable to enter the pancreas to combat the growth of tumors, creating an immune desert.

“These tumors lack quality effector immune cells that can kill them,” Yan said. “In addition, pancreatic cancer has a unique tumor microenvironment that prevents the influx of anti-tumor immune cells.”

In new research published this month in , Anne Geller, an MD/PhD student, and a research team at UofL led by Yan demonstrate that a type of beta-glucan derived from yeast can alter the environment within the pancreas to promote anti-cancer immune cell migration to the site of the cancer. Beta-glucan, a naturally occurring carbohydrate found in plants, bacteria and fungi, is known to induce trained immunity, stimulating an immune response to a specific stimulus, such as pancreatic tumor cells.

Trained immunity is a new concept in the field of immunology and is the idea that innate immune cells possess a form of “memory,” which typically only has been considered to be a feature of adaptive immune cells such as T-cells. Using animal models, Yan and his team found that when they injected particulate beta-glucan into the peritoneal area, it accumulated in the pancreas and promoted anti-cancer immune cell migration to the area. These immune cells were found to have a trained immunity phenotype and effectively inhibited pancreatic cancer growth.

“This research demonstrates that a natural compound can stimulate trained immunity in pancreas,” Yan said.

The researchers also found that beta-glucan-stimulated trained immunity can enhance PD-1 antibody therapy in pancreatic cancer. Anti-PD-1 immunotherapy has been approved to treat many types of cancer including melanoma and lung cancer. However, this therapy has failed in treating pancreatic cancer. This research could be a breakthrough in successfully applying immunotherapy to pancreatic cancer.

“This research has a great potential for clinical translation as it elucidates a strategy for delivering therapeutics directly to the pancreas, identifies a mechanism of enhancing anti-tumor immune responses against pancreatic tumors and provides insight into ways of unleashing the awesome power of immunotherapies against PDAC,” Geller said. “This could be a breakthrough in treating the deadly cancer that has evaded so many other forms of treatment.”

Yan, director of the Immuno-Oncology Program at and study coauthor, and surgical oncologist Robert C.G. Martin II are conducting a clinical trial using beta-glucan in pancreatc cancer patients as a proof-of-concept study.

“This publication demonstrates that a simple yeast-derived beta-glucan supplement has the potential to enhance a patient’s immune system and then respond more effectively to therapies in pancreatic cancer. The concept that patients’ immune systems can be ‘trained’ to see their pancreatic cancer as abnormal or foreign could be a crucial step in enhancing a patient’s overall survival and thus quality of life,” said Martin, professor and director of the UofL Division of Surgical Oncology and a co-author on the study.

According to the , more than 60,000 adults are expected to be diagnosed with pancreatic cancer in the U.S. in 2022 and nearly 50,000 patients will die from the disease. Alex Trebek, long-time host of the game show “Jeopardy!” shared his pancreatic cancer diagnosis and treatment journey beginning in 2019. Trebek died in 2020, just over 18 months after announcing his diagnosis.

“UofL is committed to solving big, global challenges through research,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This work, leveraging the power of the immune system to better treat pancreatic cancer, could have a big impact in helping people live lives that are not just longer, but healthier and more resilient.”

Yan, an immunologist and researcher with the , along with UofL Professor of Anesthesiology Jiapeng Huang and MD/PhD student Samantha Morrissey, conducted a patient study to better understand the most severe cases of COVID-19.

Approximately 20% of COVID-19 patients experience severe disease, including pneumonia and acute respiratory distress syndrome (ARDS). In some of these patients, the rapid influx of immune cells to the lungs to fight the infection leads to complications in the lung and blood coagulation disorders, resulting in heart attack, pulmonary embolism, stroke or deep vein thrombosis.

To better understand these serious complications, Yan’s team evaluated levels of various immune cells in blood samples of COVID-19 patients and compared those levels with those of healthy individuals. They discovered that one type of immune cells, low-density inflammatory neutrophils, became highly elevated in some patients whose condition became very severe. This elevation signaled a point of clinical crisis and increased likelihood of death within a few days.

Neutrophils are one type of immune cells that serve as the first line of defense in the body. When an individual acquires an infection, neutrophils rush to the site to clear the pathogen causing the infection. However, if their presence is persistent or there is a very high volume of cells at the site of infection, in this case the lungs, they can cause unwanted adverse effects. In the case of patients with severe COVID-19, a blood clotting disorder known as coagulopathy occurred, that can manifest as pulmonary embolism, heart attack or stroke.

The study, as a preprint, details shifting levels of these neutrophils and other immune cells through repeated blood samples from study participants, correlated with improvement or worsening of the patients’ condition. If clinicians could detect a rise in these cells, they may be able to provide therapy to prevent the potential life-threatening conditions associated with them.

“Based on this study, we believe that the low-density inflammatory band neutrophil population contributes to COVID-19-associated coagulopathy (CAC) and could be used as a clinical marker to monitor disease status and progression,” Yan said. “Identifying patients who are trending toward a cellular crisis and then implementing early, appropriate treatment could improve mortality rates for severe COVID-19 patients.”

To provide additional clinical options for physicians in addressing these crises, Yan is now working with other researchers at UofL to test potential therapies.