Health Sciences Research

The next chapter in cancer research

MICHAEL NISHIMURA’S CANCER IMMUNOLOGY AND IMMUNOTHERAPY LAB sits at the end of an undistinguished blue hallway in Loyola’s Cardinal Bernardin Cancer Center. If prompted, Nishimura will wander through like a gearhead, squeezing past the wooden desks to explain exactly how his machinery operates. The space has the feel of a high school chemistry classroom, only dialed up to 11. There are cell incubators whirring beside a diligent technician’s computer, something called a “bacteria bench” around another corner. Boxes of latex gloves line the steel shelving overhead.

For decades, Nishimura has studied how the immune system targets cancers. From his perch on Bernardin’s third floor, and inside the McCormick Tribune Foundation Center for Cellular Therapy, he’s embarking on some of his most ambitious work to date. Loyola is attempting to become the first hospital system in the Chicago area to engineer CAR-T cells, a kind of living drug that can be introduced into some leukemia and lymphoma patients for whom traditional treatments haven’t taken hold. Kevin Radelet, executive director of the Leukemia Research Foundation, whose organization donated $250,000 towards Loyola’s project, calls this immunotherapy potentially “groundbreaking, historic, and significant.”

Loyola, despite its size, has the right mix of ingredients to compete. In a metropolis as large as Chicago, willing to experiment with cutting-edge treatments. Nishimura’s experienced clinical partner, Dr. Patrick Stiff (MD ‘75)—tall and sober, with swept sandy hair—manages the care of those patients. The sarcastic and goateed Nishimura is an expert at building the actual cells. On top of that, he has access to the McCormick Foundation’s good manufacturing practices (GMP) facility, one of just a handful in Chicago.

The venture is part of a broader and aggressive investment into cancer research on the part of Loyola. The hematology and oncology division that Stiff oversees has more than doubled since he took over as director, in 2003. “If you can, why wouldn’t you try?” Stiff asked about the new work. “Not many places can.”

 

Finding a better treatment

The approach, though innovative, is fairly straightforward. To start, a patient’s blood is drawn. Then cancer biologists separate out the patient’s T cells, a type of white blood cell that serves as the workhorse of the immune system.

From there, using a disarmed virus, they genetically modify the T cells to produce receptors on their surface called chimeric antigen receptors, or CARs. Those receptors function like magnets, giving T cells the ability to recognize and attach to antigens on tumor cells, eventually killing them. Once engineered, the new CAR-T cells are expanded in the laboratory (into the hundreds of millions) and introduced into the sick body.


“I’ve learned that you can do almost anything if you try hard enough, if you’re persistent enough.”
— Dr. Michael Nishimura

Immunotherapies like this, which enlist and strengthen the patient’s own immune system, are relatively new in the cancer world. (Surgery, chemotherapy, and radiation are more common.) The first CAR T-cell therapy was approved by the Food and Drug Administration (FDA) in 2017; so far, it’s been restricted to tiny clinical trials nationally. Loyola was one of 22 institutions that participated in ZUMA-1, an early and successful pilot study in which CAR-T cells produced by Kite Pharma were infused into patients with large B-cell lymphoma. (Those results were published in the New England Journal of Medicine in December 2017.) And while patient responses in many of those trials have been remarkable, the prohibitive cost and the potential side effects—swelling in the brain, high fevers, memory loss, and seizures, among others—have tempered enthusiasm.

Nishimura and Stiff are confident they can make the treatment safer and more effective. They’ll do so by engineering the cells in the state-of-the-art GMP lab, a sterile room where a particulate air filtration system strips out airborne dust and microbes. One needs special training and protective clothing even to enter. “If I’m going to inject something into you,” Nishimura said, “you want it clean.”

The team at Loyola also has “a few little tricks,” most of them proprietary and gleaned over decades of experimentation and scholarship, that they hope will reduce the toxicity of the cells. A more purified product, in theory, could broaden the pool of potential CAR-T recipients by limiting the side effects and reducing the price. Stiff envisions a day when CAR-T cell therapy might become an outpatient procedure. Loyola, meanwhile, hopes to ship their cells to other medical centers, both in the region and farther afield.

During the first quarter of 2019, Stiff and Nishimura should get clearance for the first phase of their three-part clinical trial, in which they’ll treat a dozen or so willing participants. Some additional dry runs in the lab, plus what Stiff jokingly calls the “morass” of FDA approval, stand in the way. Once they feel confident they’ve designed the ideal CAR, they’ll expand the patient population. Eventually, if successful, these immunotherapies could obviate the need for bone marrow transplants, which Stiff has performed since the 1980s. To describe the team’s progress, he used the analogy of his child’s chapter books. Right now, they’re in Chapter Two, because “there’s a lot more to do before the story is fully told.”

Nishimura, for his part, knows there’s plenty more biology that needs cracking to substantially reduce the treatment’s toxicities. Each morning, he’s usually at his desk by 5:30 a.m., reviewing manuscripts in front of two freshwater fish tanks. While he studies the body’s intricate mechanics, his scaly friends flit around lazily beside him. “I’ve learned that you can do almost anything if you try hard enough, if you’re persistent enough,” Nishimura said. “Sleep is overrated.”

More about cancer treatment at Loyola

Loyola researchers are fighting cancer from every angle. Nancy Zeleznik-Le now chairs a reorganized cancer biology department, which allows 17 faculty members previously siloed in diverse clinical specialties to meet formally in meetings and seminars, sharing expertise and insight. Their study areas are as diverse as immunotherapy, cell signaling, and epigenetics. As part of Loyola Medicine’s pursuit of a National Cancer Institute Comprehensive designation, efforts are also underway to recruit some of the field’s leading scholars. Stiff appreciates his colleagues’ lack of ego; at the medical center, competing professional interests rarely interfere with the tasks at hand. “There’s really such a feeling of optimism around Loyola,” Zeleznik-Le added. “It’s actually a collaborative environment.”