At the 13th Annual Association for Value Based Cancer Care Summit in 2023, held October 18-20, 2023, in New York City, Scott Gottlieb, MD, Former Commissioner of the FDA, gave the keynote lecture on how to foster innovation in oncology.
As a blueprint for the lecture, Dr Gottlieb used his upcoming book, “The Miracle Century: Making Sense of the Cell Therapy Revolution,” which will be published in 2024. In this book, he tells the story of the development of chimeric antigen receptor (CAR)-T cells, which is a case in point demonstrating how innovative advances culminate in improved patient care.
“My objective in writing the book was to identify the factors that enable that success [of CAR-T cells] in oncology and think about how we can make sure that they can be replicated not just in other settings of cancer, but in healthcare more generally,” Dr Gottleib told attendees. “Some tail winds [from the CAR-T cell story] contribute to a bright future in oncology.”
“CAR-T cells were developed by incremental science punctuated by Eureka moments. This entailed small plodding advances that took place over 30 years and then were consolidated in the first CAR-T therapy for patients,” he explained.
Scott Gottlieb, MD
The goal is to figure out how to replicate the CAR-T success story [with other innovative therapies] in cancer and other conditions.
—Scott Gottlieb, MD
The Steps Leading to CAR-T Cells
The first step in developing modern cell therapy started with observations from bone marrow transplants. Researchers noticed that in addition to bone marrow, T cells were involved in the therapeutic efficacy.
“The next inflection point was the discovery of how to engineer T cells, by Steven Rosenberg, MD, and colleagues at the National Cancer Institute. Then came the notion to tailor T cells to fight cancer. Around the same time, tangential developments were occurring with the first gene cell therapy delivered to a patient by Dr Rosenberg. These researchers crossed the major Rubicon, by demonstrating it was safe and feasible to give a patient cell therapy,” Dr Gottleib continued.
Modern trials of the first generation of CAR-T cells were in Kaposi’s sarcoma. Second-generation trials included dual stimulation of the CAR-T cell. In the mid-1990s Michel Sadelain, MD, PhD, Stephen and Barbara Friedman Chair and Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, homed in on the addition of CD19 to CAR-T cells. And the culmination of the process of developing CAR-T cells was due to research by Carl June, MD, Richard W. Vague Professor, Immunology, Department of Pathology and Laboratory Medicine; Director, Center for Cellular Immunotherapies, Perelman School of Medicine; and Director, Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, and colleagues.
“The singular advance was in the ability to stimulate and replicate CAR-T cells outside the body and expand T cells in culture,” Dr Gottleib said.
“Dr June’s major contribution was thinking through the practical issues of how to navigate the process and integrate the components. It takes a lot of resolve and resilience to make these advances happen. CAR-T took 30 years,” he reminded listeners.
Replicating This Success
“The goal is to figure out how to replicate the CAR-T success story [with other innovative therapies] in cancer and other conditions,” Dr Gottleib noted.
He observed that it takes replication, patience, and the willingness to invest over the long term to lead to a long sequence of small discoveries that coalesce into a breakthrough.
“It takes a dedicated physician scientist at the helm [such as Carl June] to take discoveries that can result in advances in patient care. Often this resolve comes through direct patient care that provides the stamina to push through the inevitable setbacks and other impediments,” he added.
“These days, I am concerned about National Institutes of Health (NIH) funding, because it is so risk-dependent upon the NIH, and this can prevent the kind of risk-taking that is necessary in research and innovation, particularly early in the discovery cycle of a new therapy,” Dr Gottleib said.
Translational research is a critical component of bringing advances to healthcare. One needs to think through all the seemingly mundane issues, such as how to manufacture CAR-T cells on a larger scale.
“Carl June focused on building a manufacturing facility at [the University of Pennsylvania]—not just a manufacturing facility, but also a vector facility that enabled him to conduct a large clinical trial at an academic institution—because he envisioned that need and made those investments,” Dr Gottleib continued.
Another ingredient for success is also exemplified in the CAR-T cell story; that being the need for a clear regulatory framework.
“The lack of a clear regulatory framework [in other areas of medicine] is the reason we have not seen stem cell therapy proceed outside of oncology, although we have seen promise in other areas, such as neurodegenerative disease and diabetes,” he said. “It is an impediment to progress in areas of medicine where the regulatory process hasn’t been thought through and it isn’t clear how to navigate it.”
Even though I know there are a lot of obstacles, I’m optimistic about the future of oncology and particularly drug development in this setting.
—Scott Gottlieb, MD
Optimism About the Future
Despite the challenges facing innovation and breakthroughs in oncology and other medical areas, Dr Gottleib said that he is optimistic about the future.
“There is no question that there are headwinds in oncology. It is a crowded space and venture capitalists are pulling back to some degree. The Inflation Reduction Act is a major headwind as well, with impacts on programs like 340 B creating a hurdle,” he noted.
“In cancer, I have seen the explosive growth of next-generation sequencing to ensure patients are getting the right medications. In many settings, we have done the painstaking work of figuring out the biology of the disease. We are seeing the ability to intervene in diseases and attenuate pathways to interfere with cancer growth,” he explained.
“Even though I know there are a lot of obstacles, I’m optimistic about the future of oncology and particularly drug development in this setting,” Dr Gottleib concluded.