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‘We have to cure’ cancer, says CAR T pioneer Carl H. June, MD
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Carl H. June, MD, is about to receive an award for his life’s work — it's not his first and it certainly won’t be his last. Yet, he remains humble about the accolades.
All this despite being named one of Time magazine's most influential people in 2018, an honor that this professor in immunotherapy at University of Pennsylvania’s Perelman School of Medicine said he never imagined when he decided to dedicate his efforts to scientific research and, specifically, immunology.
“It’s really an overwhelming honor to receive these recognitions,” June told HemOnc Today. “My team has seen really striking results as we continue to make new kinds of [chimeric antigen report] T-cell therapies.”
June said it’s a rewarding experience when he travels to events such as the American Society for Clinical Investigation’s Harrington Prize gala, where he received the organization’s top honor. Held earlier this month, it’s one of the many events where he said patients or their loved ones approach him to express their gratitude for treatments made possible by his lab’s research.
“Both the science and medical fields are accepting this treatment and are moving forward — and very rapidly — with new kinds of innovation in this space,” June said. “To see the way the public and patients have embraced it is spectacular.”
This evening, June will receive yet another honor: the Edward Netter Leadership Award from the Alliance for Cancer Gene Therapy.
“The development and execution of anti-CD19-directed CAR T cells into clinical practice for B-cell leukemia and lymphoma will likely be the single biggest milestone I witness in my career, and it could not have happened without the wisdom, creativity and vision of Dr. June,” Caron Jacobson, MD MMSc, assistant professor of medicine at Harvard Medical School and director of the cell therapy program at Dana-Farber Cancer Institute, told HemOnc Today. “His ongoing work in the field, both in identifying new tumor targets, understanding mechanisms of resistance, and building safer and more effective engineered immune effector cells will undoubtedly lead to the expansion of this science, technology and therapy into solid tumors.
“There will be no ‘one cure’ for cancer, but finding a cure for each type of cancer is the ultimate hope and goal,” Jacobson added. “We are at a precipice, largely due to the work of Dr. June in the field of immunotherapy and cellular therapies, where there is real optimism that this hope and goal can be achieved.”
June began his career as with the goal of being a physician and caring for patients, he said.
“My career has been completely unpredictable,” he added, including “unexpected twists and turns.”
Before collecting his latest award, June, whose lab helped pioneer the development of CAR T-cell therapies for blood-based cancers, spoke with HemOnc Today about his journey, his current research and the future of cell-based therapies.
Prior lessons
June’s initial interest in being a physician came from his experience with a severe arm break and the role of his orthopedic surgeon in his recovery. His work in the lab began in medical school, and it piqued his curiosity.
“I got the idea that I could maybe make a larger contribution by working in a lab rather than seeing patients one by one,” June said. He stopped seeing patients in 1999, when he moved to University of Pennsylvania and began working on clinical trials.
June was initially drawn to the field of immunology because his mother had lupus.
He studied lupus nephritis in medical school, where his first lab work was on autoimmune disease.
June is a graduate of the U.S. Naval Academy, and part of his commitment included serving as a clinical physician. The Navy sent him to Seattle from 1983 to 1986, where he learned the new technique of bone marrow transplantation to treat leukemia.
“We found that it worked through the immune system, and it was the first kind of T-cell therapy,” June said.
This was his introduction to the power of the immune system, he said. It also was the beginning of a convergence of interests that led him to wonder whether the immune system’s power could be manipulated to treat immune diseases and cancer.
There was no single lightbulb moment when June hypothesized that genetically engineered T cells could be used to treat cancer. Think of it instead as a dimmer, starting out in darkness and gradually getting brighter with experience.
The initial click of the switch came in the early 1980s, at a moment of both loss and discovery.
“[It] was a very sad but striking case where a patient I had with leukemia received a [bone marrow] transplant and she died [of] graft-versus-host disease within about 3 weeks,” June said.
The process, whereby the immune system from the donor activates in the bone marrow recipient, could not be halted, and this immune reaction continued “despite the really potent immunosuppressive drugs we gave her,” June added.
He described the subsequent liver damage to the patient as simply awful.
“That taught me, in literally just a few weeks, that the immune system is capable of destroying,” he said.
The experience also prompted a question from within: Could we channel this same force in the immune system to fight disease, but instead use the patient’s own immune cells rather than those from a donor?
The light continued to brighten in the mid-1990s, during the HIV/AIDS epidemic, June said. During his time at the Naval Medical Research Center, he was part of the team that performed the first human T-cell transfers.
“We saw patients’ CD4 counts go up, and that was really quite remarkable,” he said. “We took cells from a patient, grew them up in a lab, and gave them back to the patient.”
The CAR T-cell process finally came fully into the light, June said, after more than 15 years of gene modification work and trials in patients with HIV or cancer. It’s a moment that June said he will never forget.
“We finally got it right in 2010, with our first CAR T patient with leukemia who had a striking regression of their disease,” he said.
At the time, he wasn’t sure if his team had finally achieved a breakthrough or was “just really lucky.”
June proudly affirmed that, more than 8 years on, the first two patients treated with tisagenlecleucel (Kymriah, Novartis) who experienced a regression of their cancers are not just in remission, but appear to be cured.
'Incredible' progress
June previously spoke with HemOnc Today about new research applying CAR T-cell therapy to pancreatic cancer. During his most recent interview, he provided updates on this research and other challenges his lab is currently working on.
Pancreatic cancer, June acknowledged, has one of the worst response rates to immunotherapy.
“It’s been unresponsive to checkpoint inhibitor therapies,” he said, adding that now “we have our first glimmers of hope in this area.”
It comes in the form of a trial being conducted at University of Pennsylvania that has enrolled six patients with metastatic pancreatic cancer for treatment with CAR T cells. One of the patients experienced complete regression of all metastatic cancer in their liver within a month of treatment.
“We have many more potent CAR T cells currently undergoing testing in the lab,” June said. “That work is going forward and it’s really promising. It will probably end up being combined with other types of immune therapies for pancreatic cancer.”
The most significant challenge facing June’s lab, and those like his around the world, is to achieve the same results in solid tumors that have been seen in hematologic malignancies.
“We have trials here at Penn in almost all the solid cancers you can think of — from brain cancer to pancreatic cancer to prostate cancer," he said.
Each of these cancers, he explained, is different and each presents unique obstacles.
“I believe there’s a bright spot in that there are many more people in this field than there were when we first started using CAR T cells, so I think the progress will be a lot more rapid,” June said.
“This is definitely the end of the beginning and the field of engineered cellular therapies is growing rapidly,” Jacobson told HemOnc Today of June’s work. “I share Dr. June’s expectation that this will expand into solid tumor oncology, where it will be as exciting as it has been for blood cancers. I am hopeful, based on the pace of research and development as well as innovation in this field, that this will be accomplished within the next decade.”
That rate of development has far outpaced anything June could have imagined.
“So far the progress has been incredible,” he noted. “I had no idea how big it would be, and it has literally catalyzed a whole new industry.
“It’s exciting to be in the early days of a new industry. It’s like being at the ground floor with Microsoft or Apple,” June added. “There are a lot of analogies with the computer and mobile device revolutions. Initially they were not available to everyone; they were really expensive. Then they rapidly got better and cheaper, and I think that’s what’s going to happen to these cell therapies.”
Future directions
When asked to look ahead a decade and predict CAR T-cell therapy’s trajectory, June’s reply was swift and firm.
“First of all, it won’t be just CAR T. There will be all kinds of engineered cell therapies. One way to predict this is that there are hundreds of biotech companies already developing engineered natural killer cells, engineered T cells, engineered stem cells, and so on. This is just the beginning.”
In an interview with HemOnc Today about June’s accomplishments, contribution to research and latest award, Stephen J. Forman, MD, Francis & Kathleen McNamara distinguished chair in hematology and hematopoietic cell transplantation and leader of the Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope, said June’s work paved the way for these additional applications of cell therapy.
“Dr. June and his group have helped to revolutionize cancer therapy by their work in developing CAR T cells for the treatment of cancer,” Forman said. “Along with others in the field, including those who worked on checkpoint inhibitors and bi-specific antibodies, they have made immunotherapy an equal partner to surgery, radiation and chemotherapy in the treatment of cancer.
“This our hope too, namely that immunotherapy will be at the front end of cancer therapy for patients with all types of cancer, and it will be achieved using many different kinds of engineered cells targeting cancer and the microenvironment of the tumor,” he added.
June predicted that for nearly all hematologic malignancies, cell-based therapy would become a first-line treatment instead of high-dose chemotherapy.
As for solid tumors, June characterized future progress using cell-based therapies as the great unknown. He believes that cell therapies, in combination with checkpoint inhibitors, can achieve greater responses in solid tumors than the 10% to 20% rates currently seen from checkpoint inhibitors alone.
“The question is, how long this process will take?” he said.
June explained that the most expensive conditions to treat in the United States are those with no definitive cure, such as diabetes or arthritis. Cancer comes in at No. 5 on the list of most expensive conditions, he said, adding that it would be even higher except that many cancers cause death so quickly.
Vaccines, early treatment and immune therapies, if they can be applied upfront, would be much cheaper than providing long-term therapies for a chronic disease, June maintained. He hopes it will one day get to that point, but once again he questions how long the process will take.
“It will get more expensive before it gets less expensive because we will initially develop therapies that prolong lives, but it will take longer to develop actual cures,” June said.
So, does Carl June, MD, really believe humankind can cure cancer?
“I think we have to cure it,” June said. “If we turned cancer into a chronic disease, it would be unaffordable. We need to find cures.” – by Drew Amorosi
For more information:
Carl H. June, MD, can be reached at University of Pennsylvania Perelman School of Medicine, 295 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104; email: cjune@upenn.edu.
Disclosure: June reports grant support from Novartis. He also holds intellectual property licensed by the University of Pennsylvania to Novartis. Jacobson reports consultant roles with Kite, Novartis and Precision Biosciences. Forman reports lab support from and a consultant role with Mustang Bio.