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 .

Support of TILs cell therapy

Half of this incredible investment in the Brown Cancer Center, $1.5 million, supports the TILs program by providing funding for research staff, supplies and faculty time dedicated to clinical trials. The goal is to increase capacity and access for participants in clinical trials for TILs and other immunotherapies.

The Brown Cancer Center is a lead enrolling center in TILs trials and has had patients travel to Louisville from all over the United States. The success of the program is directly related to the Gibbs Foundation initial investment of $1.5 million in 2022.

This philanthropic investment follows FDA approval of the cell product AMTAGVI (lifileucel), developed by Iovance Biotherapeutics for the treatment of melanoma patients. The Brown Cancer Center participated in these clinical trials leading to this FDA approval and is one of the first authorized treatment centers.

Although the initial FDA approval is specific to metastatic melanoma, the expansion of this cellular therapy to other cancers is being tested at Brown Cancer Center and elsewhere with a goal to obtain FDA approval in several solid tumor types in the future. Read more on the FDA approval in the .

Creation of Gibbs Pancreatic Cancer Research Program

Through $1.5 million over three years, the Gibbs Pancreatic Cancer Research Program will be created at the University of Louisville to support efforts in testing novel therapeutic agents for the treatment of pancreatic cancer. Five $50,000 pilot grants will be awarded to researchers each year for the development of novel therapeutics to treat pancreatic cancer and increase clinical trials dedicated to treating pancreatic cancer. This center will also provide funding for trial research staff and faculty time dedicated to these projects.

“The Gibbs Foundation is thrilled to be continuing our partnership with the Brown Cancer Center and the fight against cancer. Based on the positive outcomes of so many patients who have been through the TILs program, it is a battle we are winning,” said executive director of the Gibbs Foundation Hannah Roquet. “The creation of the Gibbs Pancreatic Cancer Research Program is especially meaningful as it continues the legacy of our founder, George Gibbs, who fought his own battle valiantly, and provides the opportunity for groundbreaking research in a cancer that has taken the lives of many too quickly and without warning.  We are looking forward to the future of this very special program.”

The Gibbs Foundation, Inc. was established in 2014 by George Gibbs of Louisville who died in 2022 of pancreatic cancer at age 87. The Gibbs Foundation previously supported health research at UofL through gifts of more than $2.5 million to create and expand the Gibbs Lung Research Program.

“The Brown Cancer Center has one goal – to end cancer,” said Jason Chesney, chief administrative officer and director of the Brown Cancer Center, who also serves as chief of the Division of Medical Oncology and Hematology at the UofL School of Medicine. “As more cancer centers across the country begin to implement TILs programs, we will be saving more lives. Through the philanthropy of the Gibbs Foundation, we continue to be one step closer to achieving this goal. Their dedication to finding a cure and increasing access to novel therapeutics is astounding.”

More information on TILs therapy and UofL Health – Brown Cancer Center is available at .

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.”

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.

The collaboration provides IN8bio exclusive access to a state-of-the-art GMP manufacturing facility and is structured to support the company’s anticipated INB-400 Phase 2 clinical program in glioblastoma.

“We are proud to be partnering with the University of Louisville, the UofL Health – Brown Cancer Center and the Dunbar CAR T-Cell Program who have been at the forefront of clinical development and patient access to novel cellular immunotherapies. One of the biggest challenges facing cell therapy companies is efficient access to high-quality manufacturing facilities with the experience and capacity required to support multicenter clinical trials and commercial manufacturing,” said Kate Rochlin, chief operating officer of IN8bio. “The Dunbar CAR T-Cell Program has a superb facility designed specifically to advance the development of promising T-cell therapies. We are excited to progress our INB-400 program towards a company-sponsored investigational new drug application that will advance this program into Phase 2.”

“Since their inception, the UofL Health – Brown Cancer Center GMP Manufacturing Facility and the Dunbar CAR T-Cell Program at the University of Louisville have been committed to bringing these lifesaving immunotherapies to adult and pediatric cancer patients throughout Kentucky and the region. This manufacturing agreement with IN8bio will allow our facility to provide these groundbreaking immunotherapies for patients throughout the United States,” said James Cripps, manager of the Brown Cancer Center GMP Manufacturing Facility.

“It is with the greatest excitement for the Evan Dunbar Foundation CAR T-cell program that we announce that IN8bio has joined us in this world-changing research,” said Thomas E. Dunbar. “Along with the amazing work at the University of Louisville, I believe that IN8bio can join with us in achieving the goals of the Evan Dunbar Foundation CAR T-cell program. These three organizations working together will create trials that will impact hundreds, if not thousands of patients.

“I am so honored and pleased to see our vision of cancer research come closer to trial and real-time treatment of patients. This has been my lifelong dream and is the most fulfilling way to honor my son, Evan Dunbar, my wife, Dr. Stephanie Altobellis, my father, Wallace and the rest of my family.”

The Dunbar CAR T-Cell Program was created in 2019 thanks to a $1-million pledge from Dunbar, a Louisville resident. It is a state-of-the-art manufacturing facility custom built to collaborate with the biotech industry to advance cutting-edge cell and gene therapies. T-cell therapies utilize immune cells that are genetically modified to fight cancer. The modified cells are infused into the patient with the goal of fighting the cancer and creating long-term immunity to delay or prevent recurrence. The facility is led by and staffed with experts in cell therapy manufacturing who will work closely with the IN8bio team to produce the DeltEx DRI cells for INB-400.

Building on more than two decades of success in cancer research, the University of Louisville is poised to advance immunotherapy with a grant of $11.5 million from the National Institute of General Medical Sciences to establish the (CCII). The new center will develop and improve strategies that use the immune response to fight cancer. The five-year grant also will allow UofL to establish the CCII as a National Institutes of Health-designated Center of Biomedical Research Excellence (CoBRE) to support young investigators and develop additional basic, translational and clinical research at the .

“One of the university’s Grand Challenges is to advance the health of all people,” said UofL President Neeli Bendapudi. “Through this center, our cancer researchers will grow the field of immunotherapy, saving the lives of many more patients with cancer in the future.”

“Our mission is to harness the power of the immune system to eradicate cancer,” said Jason Chesney, director of the Brown Cancer Center. “The University of Louisville, UofL Health and the Brown Cancer Center have been at the forefront of the clinical development of a new generation of immunotherapies that have been proven to increase the survival of cancer patients. This grant from the federal government leverages our existing strengths in cancer immunology and clinical trials to accelerate the development of new immunotherapies that will translate into lives saved across the globe.”

Cancer survivor Jeff Habermel received two different immunotherapies at Brown Cancer Center in the course of treatment for three different cancers, including metastasized melanoma.

“I consider myself very fortunate to have the type of care that Dr. Chesney and Dr. (Donald) Miller and the whole staff provide at the Brown Cancer Center. We have a world-class facility right in our backyard,” Habermel said. “I truly feel I am the luckiest man in the world to live in a time when we have such technologies and such amazing abilities to treat cancer in these ways.”

The newest cancer treatments often are available at Brown Cancer Center through clinical trials before they are available anywhere else. One such treatment is CAR T-cell therapy, in which a patient’s own immune cells known as T cells are modified in the lab to more effectively attack cancer cells. UofL announced the creation of the at UofL in October.

“Our leading-edge cancer program improves access for patients in our region, giving them the opportunity to benefit from life-saving immunotherapies through clinical trials,” said Tom Miller, CEO of UofL Health. “Thousands of our cancer patients – our neighbors and family members – are alive today because of this early focus on drugs that activate immunity against cancer.”

Researchers within the CCII will build on expertise and resources gained from previous research at UofL to develop better cancer immunotherapies. This will be achieved in part by enabling talented junior investigators who have not yet obtained major funding to advance their research and subsequently obtain major grant awards of their own.

“One of the major goals of the center is to cultivate the next generation of cancer scientists in immunology and immunotherapy,” said Jun Yan, professor, director of the CCII and chief of the UofL Division of Immunotherapy. “Starting in year two, we will call for pilot projects that will bring in more researchers and investigators to work on immunotherapy and immunology.”

The young researchers are provided funding, mentorship and access to sophisticated facilities to advance their research. Once CCII-supported researchers obtain their own funding they rotate out, allowing new investigators to come in to the program.

“It’s training a cohort of new investigators who will have their own large grants and expertise,” said Paula Bates, professor of medicine and co-investigator for the CCII along with John Trent. “We are building a critical mass of well-funded researchers in the area.”

Senior UofL faculty members Robert Mitchell, Nejat Egilmez, Haribabu Bodduluri, Huang-Ge Zhang and Bing Li will serve as mentors and core directors for the CCII. In the first year of the program, four junior researchers at UofL are conducting projects to improve the effectiveness of immune therapies.

• Chuanlin Ding is investigating the impact of chemotherapy on anti-tumor immunity in breast cancer order to discover effective combination regimens that improve conventional chemotherapy.
• Qingsheng Li is exploring a method to improve immune checkpoint inhibitor therapy for non-small cell lung cancer. Immune checkpoint inhibitors are a type of immunotherapy that blocks proteins (checkpoints) made by immune system cells, such as T cells. The checkpoints can prevent T cells from attacking cancer cells.
• Corey Watson is studying immune cells to determine which of these cells are beneficial to lung cancer patient outcomes and how they may help kill tumor cells.
• Kavitha Yaddanapuddi is studying immune checkpoint inhibitor resistance in lung cancer patients. This will help in developing therapies that reduce resistance and improve treatment.

This grant may be extended for two additional five-year phases. A previous CoBRE program for cancer research at UofL was extended through all three phases, lasting 15 years. That program significantly expanded the contingent of both junior and senior investigators at UofL, including Chesney, Trent and others whose research was funded by the previous program.

“This type of funding has been truly transformative for this cancer center,” Trent said. “The research for the current generation of immunotherapeutic checkpoint inhibitors was done more than 18 years ago. This grant’s research will feed into the clinical work in time. These grants lay the groundwork for the next generation of therapies.”

To extend the impact of the CCII still further, Kosair Charities has provided an additional $200,000 to facilitate the discovery and development of immunotherapy drugs for children with cancer. This gift bridges the CCII and the UofL Kosair Charities Pediatric Oncology Research Program, allowing the CCII to focus also on immuno-oncology for children.

“Kosair Charities is proud to be the first community partner to support the UofL Center for Cancer Immunology and Immunotherapy,” said Kosair Charities President Keith Inman. “The UofL Kosair Charities Pediatric Cancer Research Program will allow this new center to include crucial pediatric cancer research as well as expand the scope to all people living with cancer – children and adults alike.”

The new program will be named the Dunbar CAR T-Cell Program.

“This gift will allow both kids and adults to be treated right here in Kentucky with the most innovative cell-based immunotherapy being developed,” said Jason Chesney, MD, PhD, director of the UofL Brown Cancer Center.

In CAR T-cell therapies, immune cells are extracted from the patient’s own blood and then are genetically modified to fight cancer. The modified cells are infused back into the patient where they fight the cancer and create long-term immunity to its recurrence. In addition to dramatic treatment results, CAR T-cell immunotherapy leads to fewer toxic side effects than traditional chemotherapy.

“Patients who have been treated with all the conventional therapies who then underwent treatment in clinical trials with CAR T cells had dramatic response rates. Eighty-three percent of kids in the original trial who had lethal, terminal B-cell acute lymphoblastic leukemia responded to this therapy,” Chesney said.

CAR T-cell therapy is FDA approved for treating patients who have B-cell acute lymphoblastic leukemia, who are mostly children, as well as adults who have an adult form of a B-cell (non-Hodgkin’s) lymphoma. This technology also is being tested for treatment of other cancers through clinical trials. Until now however, these treatments have been available primarily in larger coastal cities outside of the Midwestern United States.

“At the UofL Brown Cancer Center, we feel strongly that these advanced therapies should be available not just to people in New York or California or Texas, but to people in Kentucky, Indiana, Tennessee and Illinois. If you live in these areas, it is going to be very hard for you to be treated a thousand miles away with a therapy like this,” Chesney said. “And any patient with health assistance through Medicaid is likely to be covered only if the treatment is delivered within the state.”

The Dunbar CAR T-Cell Program will include laboratories for manufacturing the CAR T cells and will administer both FDA-approved and clinical-trial therapies to adult and pediatric cancer patients. The program intends to expand clinical trials and clinical research using CAR T-cell therapy to treat additional cancer types in Louisville. The goal is for the facilities to be fully functional and receiving patients by Sept. 30, 2020.

Tom Dunbar’s son, Evan, lost his battle to cancer with neuroblastoma in 2001 at the age of 6. In 2009, Wally Dunbar, Tom Dunbar’s father, lost his battle with melanoma. This year, Tom’s physician wife, Stephanie Altobellis, M.D., helped identify his own cancer.

“Kentucky is at ground zero, with the nation’s highest rates of cancer diagnosis and death,” Tom Dunbar said. “It’s completely unacceptable. We have to lead the charge right here where the need is the greatest and we can do the most good. We need treatments that are not toxic. Watching our loved ones miserable with pain, often just from the treatments, and yet still die in front of us simply can’t be the best that we can do.”

How CAR T cells work

T cells are key immune cells in the body that attack cancer cells. CAR T cells are T cells that have been isolated from the patient’s blood and then genetically modified to more effectively destroy the cancer cells.

A non-infectious virus is used to insert genes into the T cells that express a receptor specific to proteins, or antigens, present on cells of the cancer to be treated. The armed, loaded T cell is drawn into close proximity to the cancer cell, and the new cell sends a signal for the T cell to kill the cancer cell.

“We add the receptor gene into the T cells, which makes them stick to the cancer cells like Velcro,” Chesney said. “In theory, all cancers have unique antigens on their surface that we can target with this approach. We are nudging the immune system on to really hit the target, in this case the cancer cells.”

The sophisticated technology requires the use of a specialized clean room for genetically manipulating the patients’ immune cells. The clean rooms, known as Good Manufacturing Practice (GMP) laboratories, require specialized documentation and equipment to protect the individuals working there and ensure a sterile and controlled environment for the cells.

The Dunbar CAR T-Cell Program will include two GMP laboratories, one for use in pediatric therapies to be named for Evan Dunbar and one for adult therapies to be named for Altobellis. These labs are intended to support not only clinical trials and patient treatment at the UofL Brown Cancer Center, but also in other health centers in Louisville, Lexington and elsewhere.

“Our goal for the Dunbar CAR T-Cell Program GMP labs is to be a hub manufacturing facility for CAR T cells, not just in Kentucky, not just in the region, but for the entire country,” Chesney said.

For Dunbar, the goal is to improve cancer treatment for patients.

“The burden is on each of us to create a better future for our children,” Dunbar said. “Working together, we can ensure Louisville is equipped to provide the durable cures, free of side-effects, that we desperately need.”

Check out the video:

The recombinant protein molecule SA-4-1BBL has been used to enhance the therapeutic efficacy of cancer vaccines with success in pre-clinical animal models. It accomplishes this by boosting the effectiveness of CD8⁺ T cells, adaptive immune cells trained to target the tumor for destruction. Surprisingly, when the researchers treated normal healthy mice with SA-4-1BBL alone, the mice were protected when the researchers later exposed them to different types of tumor cells.

“The novelty we are reporting is the ability of this molecule to generate an immune response that patrols the body for the presence of rare tumor cells and to eliminate cancer before it takes hold in the body,” said , professor in the UofL Department of Microbiology and Immunology and the UofL Institute for Cellular Therapeutics. “Generally, the immune system will need to be exposed to the tumor, recognize the tumor as dangerous, and then generate an adaptive and tumor-specific response to eliminate the tumor that it recognizes. Thus, our new finding is very surprising because the immune system has not seen a tumor, so the response is not to the presence of a tumor.”

The researchers have determined that the molecule generates a tumor immune surveillance system through activation of what are known as CD4⁺ T cells and innate NK cells, thereby protecting the mice against various cancer types they have never had. This function is an indication of the molecule’s effectiveness in cancer immunoprevention.

In the research, published today in , mice that had never had cancer were treated with SA-4-1BBL alone, then challenged with cervical and lung cancer tumor cells at various time intervals. The mice showed significant protection against tumor development, with the greatest protection when challenged two weeks after treatment with SA-4-1BBL. The cancer immunoprevention effect generated by SA-4-1BBL lasted more than eight weeks.

“Just giving SA-4-1BBL alone prevents the formation of tumors in animal models,” Shirwan said. “To our knowledge, this is the first study to demonstrate that an immune checkpoint stimulator, known for its function for adaptive immunity, as a single agent can activate an immune system surveillance mechanism for protection against various tumor types.”

Additional testing showed that CD8⁺ T cells were not required for the protection, but when CD4⁺ T and NK cells were eliminated in the mice, protection failed, indicating these two cell types were necessary to achieve the effect. The lack of necessity for CD8⁺ T cells indicates the process is not one of conventional acquired immunity.

Although the research, which was conducted in collaboration with FasCure Therapeutics, LLC, tested the mice for cervical and lung cancers, the protective function of SA-4-1BBL works without context of specific tumor antigens, giving it the potential to be effective in preventing any number of tumor types.

“We are very excited about the cancer immunoprevention possibilities of this molecule. Its effectiveness is not tumor specific, and as a natural ligand, it does not cause toxicity, as is found with 4-1BB agonist antibodies. Plus, the fear of autoimmunity is highly minimized, as evident from our data, because it is activating the innate immune cells,” said associate professor at UofL and co-author of the study.

Immune checkpoint stimulators and inhibitors are major regulators of the immune system and work in a similar fashion to the “brake” and “gas” pedals in a vehicle. Cancer evades the immune system by various means, including immune checkpoint inhibitors, which apply the brake on the immune response against a tumor. Stimulators, on the other hand, serve the accelerator function, improving immune responses against cancer.

Drugs to block the action of immune checkpoint inhibitors already have shown therapeutic efficacy for several cancer types in the clinic and are approved by the Food and Drug Administration (FDA). According to Shirwan, the focus now is on immune checkpoint stimulators.

“Several antibody molecules are in clinical testing for cancer immunotherapy as immune checkpoint stimulators. However, nothing so far is approved by the FDA that gives a positive signal to the T cells,” Shirwan said. “The immune checkpoint inhibitors take the foot off the brake, so to speak. This ligand, as an immune checkpoint stimulator, puts the gas on the immune system to destroy the tumor.

“Another big surprise is that an antibody to the same receptor targeted by SA-4-1BBL did not protect against tumors, demonstrating unique and desired features of SA-4-1BBL for caner immunoprevention.”

Shirwan and Yolcu plan to conduct further tests for SA-4-1BBL in cancer immunoprevention.

“Although the notion of cancer immunoprevention is an attractive one, the design of clinical trials presents a challenge with respect to the target population,” Shirwan said. “However, with advances in cancer screening technologies and genetic tools to identify high-risk individuals, we ultimately are hoping to have the opportunity to test the SA-4-1BBL molecule for immunoprevention in individuals who are predisposed to certain cancers, as well as in the presence of precancerous lesions.”

To encourage and accelerate research in cancer prevention, the National Institutes of Health have created a network for research into immunoprevention, outlining possible methods for testing promising preventive substances and provided opportunities for associated funding. The Immuno-Oncology Translational Network is designed to create a fertile environment for research and to facilitate cancer immunoprevention research projects focusing on people who are genetically predisposed to certain cancers, those who have been diagnosed with pre-malignant lesions or polyps, and individuals exposed to cancer-causing substances, such as smokers and asbestos workers.

Check out more about this research below:

, New York Times bestselling author of “The Good Nurse,” and , a cancer researcher at the University of Chicago, will discuss Graeber’s new book, “The Breakthrough: Immunotherapy and the Race to Cure Cancer.” The book examines the ways in which cancer proliferates by avoiding the immune system, and the important new cancer immunotherapies that are beginning to unleash the immune system to fight – and beat –  the disease. 

Following the discussion, a question-and-answer session will be held.

Lunch will be provided at the seminar at no cost but seating is limited. 

At 6 p.m. on the same date, the Kentucky Author Forum will present Graeber and Gajewski at the Kentucky Center for the Performing Arts, 501 S. Main St. Several admission packages are available. Details can be found on the Kentucky Author Forum