From the Bench to the Bedside
To Develop New Immunotherapies, Collaboration Is Key
by Gaius J. Augustus, UA Cancer Center
Originally published in the Spring 2018 issue of Act Against Cancer
With more than 200 clinical trials being conducted at the University of Arizona Cancer Center, Clinical Trials Office Director Daniel Persky, MD, is a busy man. Among these trials are a growing number of studies evaluating the effectiveness of immunotherapy, a type of treatment generating a lot of excitement among physicians running clinical trials.
“The hopes of immunotherapy are extremely bright right now,” says Dr. Persky. “In many patients whose disease would have been judged to be fairly hopeless, there are no signs of the disease coming back after a year or so.”
Where are these new treatment options coming from? They don’t appear out of thin air. Over the course of many decades, they are slowly developed through a process called “bench to bedside,” where findings from the laboratory (“bench”) can develop into treatments in the clinic or hospital (“bedside”). This process starts with basic scientists like immunologists, who specialize in investigating how the body’s immune system protects us from threats — and why it sometimes is unable to do so.
Michael Kuhns, PhD, an associate professor of immunobiology at the UA College of Medicine – Tucson, explains that basic science is “like understanding how a machine or a car works. If you understand how the gears work together, you might be able to modify the function or engineer new designs.”
A firm grasp of how the immune system naturally responds to threats can identify weapons we can add to our therapeutic arsenal. When a potential opportunity for therapy, such as a drug target, is revealed by experiments, testing in cell cultures and mice is used to identify treatment options. If a potential treatment shows promise, scientists work with physicians to create a clinical trial to bring it to patients in the clinic.
Thanks to its reach into both academia and the clinic, the University of Arizona is uniquely poised to bring brilliant minds from multiple disciplines together into fruitful collaborations. Julie Bauman, MD, MPH, UA Cancer Center division chief of hematology and oncology, understands that a strong relationship between the lab and the clinic is necessary for the development of new cancer treatments.
“There are so many exciting directions to go in cancer research,” says Dr. Bauman. “We simply can’t follow every pathway, and we can’t conduct every clinical trial. To prioritize, we must have close partnerships between the laboratory and the clinic.”
‘The Bench’: Understanding the immune system
Scientists often begin by trying to understand how things work in the body under normal circumstances and how those mechanisms break down in the face of diseases such as cancer.
“If we want to understand the molecular basis for a disease or how to fight a disease, we have to do basic research to understand how that disease comes about, or how the body can naturally take care of that disease,” explains Dr. Kuhns.
Dr. Kuhns’ research focuses on understanding and manipulating the “conversations” between T cells and the rest of the immune system. T cells are able to respond to threats and coordinate attacks, and Dr. Kuhns says manipulating these messages can change the behavior of a T cell.
Dr. Kuhns reports that his team already has achieved success in a basic lab setting. “I can redirect T cells to kill targets,” he says. “One day, that could have immunotherapeutic applications.”
Thalachallour Mohanakumar, PhD (“Dr. Kumar”), research professor at the UA College of Medicine – Phoenix, has been working in the field of immunology for 40 years, focusing on transplantation. Dr. Kumar explains that when a transplanted organ is stressed, it releases small molecules into the bloodstream. His lab is interested in learning more about the immune response evoked by these molecules, which will add to our expanding body of knowledge around the immune system.
Dr. Kumar acknowledges that the progress we’ve made in fighting cancer is possible because of a growing understanding of how the immune system works. “The immune system is much more complicated than we initially thought,” Dr. Kumar explains. “Continued understanding of the immune mechanism is important, not only for cancer, but also for autoimmune disease and transplantation.”
‘Bench to Bedside’: Getting basic research into the clinic
The research done by Protul Shrikant, PhD, professor of immunobiology at the UA College of Medicine – Tucson, is a great example of how the knowledge we gain from basic immunology is essential to cancer treatment. “In fact,” he explains, “immunotherapy treatment must be based on a fundamental understanding of immunology.”
Dr. Shrikant’s basic research focuses on how T cells recognize and destroy cancer cells. The insights gained into the immune system at the basic level are then brought to clinicians.
“Our laboratory studies span from detailed understanding of fundamental immunology, to validating in animal models, to early-phase clinical trials,” Dr. Shrikant says of the ongoing work in his laboratory.
Daruka Mahadevan, MD, PhD, is the director of the UA Cancer Center Early Phase Clinical Trials Program, and specializes in the development of drugs for lymphomas, including peripheral T-cell non-Hodgkin lymphoma (PTCL), a cancer of the T cells.
“PTCL is an aggressive form of lymphoma, and we don’t have any good treatments,” Dr. Mahadevan says. Because immunotherapy harnesses the power of T cells, T-cell lymphoma is an especially challenging target. “The very cells that we are trying to activate are the cells that are abnormal,” he explains.
Dr. Mahadevan has identified a combination treatment that is effective against PTCL tumors growing in lab mice. While the immune system is suppressed in these lymphomas, his team has been able to wake the immune system back up by blocking the ability of cancer cells to divide, significantly improving the survival of these mice. He now is working with drug companies and the National Institutes of Health in hopes of finding a combination that works in patients.
“Between 25 and 30 percent of patients respond to checkpoint inhibitors, but about 70 percent don’t respond,” says Dr. Mahadevan. He believes the answer to treating this 70 percent lies in finding combinations of treatments, such as checkpoint inhibitors, which activate T cells, and targeted drugs, which attack cancer cells with less harm to normal cells.
Going backward: Bedside to bench
The journey from bench to bedside is not one way, and the University of Arizona offers a crossroads for a variety of scientists and physicians with diverse expertise to share insights and produce unique therapies. Dr. Shrikant relies on his relationships with clinicians to guide his lab’s research, often using observations from the clinic to decide what to study in the lab.
“We go back from the bedside to the bench,” says Dr. Shrikant. “My clinical colleagues constantly educate me as to what are the right questions to ask and how to pose them. The information gained by testing a well-considered hypothesis can meet an unmet need in the clinic and change the standard of care, which is extremely satisfying.”
Drawing from more than 20 years of research into fundamental cancer immunology, Dr. Shrikant enjoys making a difference in patients’ lives.
“I am constantly developing my abilities to move between basic science and the clinic in a seamless manner so as to make an impact on cancer,” Dr. Shrikant says.
“If you want to know what the potential clinical problems are, you need to work with clinical people,” says Dr. Kumar. “It’s important for the clinical people to come and tell us, ‘These are the problems, and we need to solve this.’ ”
Dr. Mahadevan agrees.
“I enjoy being in the lab and in the clinic,” says Dr. Mahadevan. “I’m able to bring questions from the clinic into the lab — and, hopefully, from the lab back into the clinic at some point.”
Dr. Mahadevan doesn’t believe in keeping scientists at the bench separated from physicians in the clinic.
“Every single person in my lab has shadowed me in the clinic or in the hospital,” Dr. Mahadevan says. “They’re not just thinking about cells and mice. They’re also thinking about the patient.”
Collaboration at the UA Cancer Center
If there are any downsides to the research being produced by scientists around the world, it’s that it’s yielding an embarrassment of riches. Physicians running clinical trials might be overwhelmed with options.
“We’re struggling with how to deal with this pharmacologic buffet,” says Dr. Persky, the Clinical Trials Office’s director. “There are so many different drugs against many targets. Judging which combination to give becomes harder to figure out.”
“We have more data than we know what to do with,” adds Dr. Bauman.
Fortunately, scientists at the University of Arizona and physician-scientists at the UA Cancer Center have built a strong relationship that is poised to push forward our understanding of the immune system and how we can improve its ability to detect and kill cancer cells. Partnerships like those seen at the University of Arizona have made the journey from the bench to the bedside faster.
Photo 1: Members of the Kuhns Lab study the "conversations" between T cells and the rest of the immune system. From left to right: Heather Parrish, PhD; Michael Kuhns, PhD; Katrina Lichauco and Mark Lee (Kris Hanning, UAHS BioCommunications)
Graphic: New cancer treatments arise from a strong partnership between the laboratory and the clinic. Each link in this chain addresses different but important questions, accelerating the development of new drugs. (Gaius J. Augustus)
Photo 2: Daruka Mahadevan, MD, PhD, and Eric Weterings, PhD, examine a petri dish in a UA Cancer Center laboratory (Kris Hanning, UAHS BioCommunications)
Photo 3: Protul Shrikant, PhD (Anna C. Christensen, UA Cancer Center)
Photo 4: Mark Lee, left, and Katrina Lichauco are graduate students in the Kuhns Lab (Kris Hanning, UAHS BioCommunications)