But in 2021, traveling west on Interstate 10 toward New Orleans, he found it impossible to pass any rest areas without taking a bathroom break.

“I realized something was off,” says the Waldo, Florida, resident. “It shouldn’t have taken me that long, but sometimes you don’t think about it when you’re drinking a bunch of liquids.”

After visiting an emergency care clinic, whose staff referred him to University of Florida Health Shands Hospital for a more in-depth look, doctors diagnosed Hill with bladder and metastatic prostate cancers. Soon after, he began treatment.

Though he had a lot of support from his family during his chemotherapy treatments, side effects prevented Hill, a retired educator, from participating in his regular activities, like coaching baseball at Oak Hall School. When his bladder cancer did not show signs of improvement through chemo and a medication regimen, his doctors scheduled Hill to undergo a full cystectomy — complete bladder removal surgery.

Usually one of the last treatment options suggested for bladder cancer, UF Health Shands expert surgeons like Padraic O’Malley, M.Sc., M.D., FRCSC, perform about 100 partial or full bladder removal procedures each year.

This irreversible procedure results in a lifetime of increased risks, which can include kidney stones, frequent urinary tract infections, and incontinence. The urinary ostomy bags, or bladder bags, required for patients after surgery must be switched out as often as every 45 minutes to every few hours for new users — disrupting sleep, travel, and daily activities.

Thanks to new research from the Department of Urology at the UF College of Medicine, O’Malley, the chief of urologic oncology and a clinical associate professor, has hope that even the most aggressive bladder cancers may someday be effectively treated by harnessing the body’s own immune system, with fewer side effects and lifestyle interruptions than ever.

“What may be the most exciting thing about this new therapy is that the target is mainly disease agnostic,” O’Malley says. “I suspect this is something we can use in several other types of cancer, not just bladder cancer.”

Over the next five years, a recent $2.5 million grant from the 1923 Fund, a private foundation, will help UF researchers Sergei Kusmartsev, Ph.D., and William Donelan, Ph.D., develop the team and resources needed to continue research on novel immunotherapy treatments for bladder cancer.

The goal: to bring a promising new treatment option to the U.S. Food and Drug Administration for approval and begin clinical trials in the next few years.

“This grant gives us a lot of freedom to expand our preclinical research, hire people, and buy the equipment necessary to develop treatments people may use in the future,” says Kusmartsev, an assistant professor in the Department of Urology, who has spent his career conducting research that gets us closer to using immunotherapies for cancer treatment.

To promote tumor growth, cancerous cells can hijack blood cells that originate in bone marrow, called myeloid cells, as well as macrophages — white blood cells in the immune system whose primary role is to clear out dead cells. This allows the tumor to spread throughout the body, a process called metastasis.

Advanced and metastatic bladder cancer is highly resistant to existing therapies, including chemotherapy. About 90% of cancer mortality occurs due to metastasis, says Donelan, a research assistant scientist in the Department of Urology.

In 2021, Kusmartsev, Donelan, and Paul Crispen, M.D., the David A. Cofrin Endowed Chair of Urologic Oncology at the UF College of Medicine and associate director for clinical research at the National Cancer Institute-designated UF Health Cancer Center, published research in the journal Cancer Research identifying the tumor-protective role of an enzyme called hyaluronidase-2, or Hyal2, in myeloid cells. Hyal2 is responsible for degrading hyaluronic acid.

“We believe the cancer is breaking down the hyaluronic acid into small fragments that give an immunosuppressive signal, recruiting the myeloid cells from the bone marrow to come to the tumor and protect it,” Donelan says.

UF’s initial breakthrough research on Hyal2 showcased the role the enzyme might play in promoting tumor growth. Now, Kusmartsev and Donelan are collaborating with UF melanoma researchers to modify and improve a type of immunotherapy called antibody-drug conjugates.

Antibody-drug conjugates, or ADCs, have been referred to as “biological missiles” by the scientific community. Employing a similar strategy to that used by cancer cells to recruit and hijack myeloid cells to support tumor growth, ADCs can bind monoclonal antibodies to specific proteins or receptors on cells — in this case, to the Hyal2 enzyme on the myeloid cells — to deliver toxic drugs that kill target cells. This prevents myeloid cells from becoming commandeered and allows the immune system to respond to invading cancer cells.

UF’s research on immunosuppressed mouse models with ADCs for bladder cancer tumors has proved extremely promising. Studies show that targeting Hyal2-expressing cells increased the effectiveness of the body’s immune cells, enabling them to discover and discard cancer cells. As a bonus, the immune system learned to prevent those cancers from returning.

Sometimes, tumor growth was so rampant among mice in their studies that even Donelan said he initially doubted the potential for the treatment’s efficacy. But entering the lab in the days following treatment, he’s been surprised on more than one occasion to find that, like a discarded apple core, the tumor first softens, then gradually shrinks, and shrinks, and shrinks, until it’s gone. The process can take as little as a week.

“It’s exciting to see this stuff actually happen in real time,” Donelan says. “We watch the tumors grow, and when we give the therapy, it’s amazing every day to watch the tumor shrink and eventually be eradicated.”

Research published by UF has supported 100% bladder cancer tumor elimination among medium-sized tumors, and 80% elimination among advanced tumors in mice models.

If such conditions can be replicated in people, the implications could be transformative for hundreds of thousands of cancer patients, particularly those with solid tumor cancers like bladder cancer. Other solid tumor cancers include colorectal, liver, and ovarian cancers.

These tumors share similar characteristics and require different types of treatment than cancers that do not form solid tumors, such as leukemia and lymphomas. And by relying on the body’s own immune cells, these treatment options have traditionally led to fewer side effects than chemotherapy alone.

O’Malley, the urologic oncology surgeon, is hopeful that ADCs, along with immunotherapy, can provide a “one-two punch” treatment for the most aggressive bladder cancer tumors. The two therapies work synergistically, he says, and each can enhance the other’s effectiveness.

“If for some reason the cancer came back down the road, your immune system would have a memory of it and kind of mop it up, potentially preventing the cancer from becoming anything major, because there’s an immune response that prevents them from taking seed and growing,” O’Malley says. “By targeting the drug using the antibody, we create a silver bullet.”

As the benches in Kusmartsev and Donelan’s lab fill to include more researchers over the next couple of years, the scientists are optimistic that new treatment options may soon result in fewer deaths and lifestyle disruptions from bladder cancer.

“Receiving this grant from the 1923 Fund is pivotal in advancing our research to overcome immunotherapy resistance in patients with bladder cancer,” Kusmartsev says. “This support will significantly accelerate the development of new therapies that will bring us closer to improving lives.”

Hill, the bladder cancer patient treated at UF Health, still takes daily medications for his prostate cancer and has monthly checkups with his care team. Though he couldn’t walk for months after his cystectomy, he can now do almost anything, with some modifications and planning.

One of his favorite pastimes remains coaching Oak Hall baseball, though he can’t be as hands-on as he used to be. Through trial and error, he’s found bladder bags that work well for him, allowing him to travel from home to Tallahassee before changing a bag out.

Hill says he’s elated for future bladder cancer patients who may someday have access to additional treatment options.

“Right now, there’s someone in Tallahassee, in Miami, in Georgia, who’s going through the same thing as me or about to get this diagnosis,” he says. “And I think if an option like this becomes available, a new person going through what I went through will feel more like themselves.”