Honoring a life scientist’s life-saving science

In his acceptance speech for the 2024 Breakthrough Prize in Life Sciences, Carl June, a pioneer in cancer treatment, highlighted the people most affected by his groundbreaking work developing CAR T cell immunotherapy: the patients.

When all other cancer treatments failed them, said June, "instead of giving up, they pushed forward and volunteered for an unproven experimental new treatment. It's because of these brave volunteers like our first patients Doug Olson, Bob Levis, and Emily Whitehead, that we have now treated over 34,000 cancer patients."

June, the the Richard W. Vague Professor in Immunotherapy in Penn's Perelman School of Medicine and director of the Center for Cellular Immunotherapies (CCI) at Penn Medicine's Abramson Cancer Center, was honored at the 10th Breakthrough Prize awards ceremony for the development of chimeric antigen receptor (CAR) T cell immunotherapy. This is a cancer treatment approach in which each patient's T cells are modified to target and kill their cancer cells.

Held on Saturday, April 13, and nicknamed the "Oscars of Science," world-renowned researchers exchanged lab coats for tuxedos at the star-studded Breakthrough Prize awards ceremony hosted by Emmy Award-winning actor and comedian James Corden. Actors Olivia Wilde and Regina King handed June and his co-winner, Michel Sadelain of Memorial Sloan Kettering Cancer Center, the awards.

"We're so grateful to have some recognition for a lot of years of work on cancer research," said June at the event. "I think the best thing is that people learn about this, that this came out of research right here in the country. Now there's been 34,000 people treated and it just started 10 years ago so people need to understand the value of research to make these new breakthrough therapies."

Interim President J. Larry Jameson attended the award ceremony to help celebrate his Penn Medicine colleague June. "All of us at Penn are extremely proud to see him recognized with such a high honor," said Jameson. "Dr. June's foundational work has not only brought hope and life to cancer patients. He has also helped transform Penn and Philadelphia into a hub for cell and gene therapy research, teaching, and innovation. I think we all can expect many more breakthroughs to come."

Founded in 2012, the Breakthrough Prizes are the world's largest science awards, with $3 million awarded for each of the five main prize categories. June, also the the director of the Parker Institute for Cancer Immunotherapy, is the sixth Breakthrough Prize laureate from Penn, joining physicists Charles Kane and Eugene Mele of the School of Arts & Sciences, and Alzheimer's researcher Virginia M-Y Lee, and mRNA pioneers Katalin Karikó and Drew Weissman, all of the Perelman School of Medicine.

The road to CAR T

June, a California native raised in the Bay area, sought to follow in his father's footsteps and study chemistry after graduating high school in 1971, but his academic path took an unanticipated turn with a low draft number during the Vietnam War. Although he was accepted to Stanford, where he intended to pursue his undergraduate studies, June instead enrolled in the U.S. Naval Academy, where he graduated with a degree in biology.

The War drew to a close around the time he completed his undergraduate studies in 1975, which afforded June an opportunity to attend the Baylor College of Medicine in Houston, courtesy of a scholarship from the Navy.

Throughout his medical training, and owing to his mother's lupus diagnosis, June grew increasingly interested in research and immunology, which guided his subsequent career choices. "I began working an immunology lab in medical school studying immune complexes," said June in an interview with the American Society of Gene + Cell Therapy. "Then I was able to go to Switzerland for a year and work for the World Health Organization [WHO], and I worked there on the immunology of malaria."

Following his work at the WHO, June did a four-year residency as part of his medical training at the National Naval Medical Center. He learned to perform bone marrow transplants, which is considered a form of immunotherapy, at the Fred Hutchinson Cancer Center [the Hutch], where June began to study T cell activation.

T cells are a type of lymphocyte, which are a subtype of white blood cells, that play a central role in the immune response, and June and his colleagues at the Hutch began exploring ways to manipulate them. Although he was a licensed oncologist at the time, June was still working for the Navy and the only research they were funding in the medical space was to treat combat casualty care and infectious disease. In a retrospective article for Human Gene Therapy, June described this as "a proverbial blessing in disguise," as he was forced to learn about virology, leading to the discovery of new viruses-human herpes virus 6 and 7-and insights with HIV that later aided in studies for cancer patients.

In particular, June and colleagues were working with antibodies against the protein CD28, which is found on the surface of T cells and acts as a co-receptor for the cells' activation. While studying HIV, June worked to understand how the virus integrates into the host's DNA and remains latent. His work also included discoveries on how to grow T cells from AIDS patients, which was challenging due to the weakened immune system of these patients. This involved manipulating T cells outside the body and enhancing their growth using CD28 co-stimulatory molecules-techniques that would later be vital for Chimeric Antigen Receptor T cell (CAR T) therapy.

June and colleagues including Penn Medicine's Bruce Levine, who was June's postdoctoral researcher at the time, later partnered with Cell Genesys, a former San Francisco biotech company, to conduct the first randomized trial with gene-modified T cells in patients with HIV in the late 1990s. These trials demonstrated both the safety and feasibility of CAR T, as well as improved immune function in patients with HIV, marking a novel therapeutic paradigm for disease.

Transferring techniques to tackle cancer

June concluded his service to the Navy in 1996 and was later recruited to Penn, where he continued his work on HIV, and also expanded upon his expertise in immunology to take on cancer.

In oncology, June sought to leverage skills he had developed in gene therapy and T cell manipulation and adapted the strategies used in HIV research to engineer T cells that could specifically recognize and attack cancer cells. At that time, immunotherapy was a nascent field in oncology, with minimal funding and only a few labs exploring its potential.

Recognizing the transformative potential of this approach, but facing limited traditional funding avenues, June and his colleagues received crucial support from philanthropists like Barbara and Edward Netter and organizations like the Leukemia and Lymphoma Society. The Netters formed the Alliance for Cancer Gene Therapy (ACGT), which played a pivotal role in supporting early research in this area.

ACGT provided funding for pilot trials that were critical in advancing the development of CAR T cell therapies and their support helped bridge the gap between innovative academic research and its clinical application, which often requires substantial financial resources not readily available through conventional funding channels. These trials yielded impressive results, particularly in patients with advanced leukemias, leading to significant advancements in the treatment of these cancers.

"When we finally infused our first patients in 2010, the results were breathtaking," wrote June. "Two of three patients with end-stage advanced leukemia achieved a complete remission that is lasting more than four years since infusion; the third patient had a partial response."

Breaking through

Following the success of the initial adult patients treated with CAR T cell therapy, wherein June and colleagues saw long-term efficacy, the team at Penn received approval to begin treating the first pediatric patient with refractory acute lymphoblastic leukemia (ALL), under the care of Stephan Grupp of the Children's Hospital of Philadelphia (CHOP).

In April 2012, Emily Whitehead, a six-year-old diagnosed with ALL, enrolled in the experimental treatment using CAR T-cell therapy. Prior to treatment, Whitehead had experienced two relapses, with her cancer failing to respond to conventional therapeutics, causing her condition to become life-threatening.

At the beginning of the trial, her T cells were extracted, then modified with CAR that targeted CD19, another cell-surface protein that plays a role in immune response, and finally infused in her body. Complications initially arose as the treatment triggered a severe immune response known as a cytokine release syndrome, or cytokine storm, wherein the rapid destruction of cancer cells by the immune system leads to high fever and flu-like symptoms, a common side effect of CAR T cell therapy. Whitehead's condition worsened as she experienced multiple organ failure and difficulty breathing, resulting in her being placed in the pediatric intensive care unit.

The Penn and CHOP researchers, however, found through laboratory analysis that there were extraordinarily high levels of a particular inflammatory cytokine known as IL-6 in Whitehead's blood. June, who had a personal connection to IL-6 inhibition due to his daughter's treatment for juvenile rheumatoid arthritis, was uniquely familiar with tocilizumab-a drug approved by the FDA to block the action of IL-6. This understanding led the team to urgently administer tocilizumab to Emily. The intervention was effective, rapidly improving her fever and stabilizing her organ functions, and led to Whitehead's cancer going into remission.

The success of Whitehead's treatment contributed to the eventual FDA approval of the first CAR T cell therapy, Kymriah by Novartis, in 2017 for children and young adults with refractory or relapsed B-cell precursor ALL. This was a landmark approval, which has since paved the way for further approvals of CAR T cell therapies for other types of cancer, and Whitehead, who is now a first-year student in Penn's College of Arts and Sciences, has been cancer-free for more than a decade.

The battle presses on

In the years following June's pioneering research on CAR T-cell therapy, the field has seen remarkable growth and diversification. Today, there are six FDA-approved CAR T cell therapies approved for treating blood cancers and hundreds of clinical trials involving CAR T cell therapies taking place globally, reflecting the widespread interest and potential applications of this treatment. June's laboratory, along with the team at the Center for Cellular Immunotherapies (CCI), remains at the forefront of this research, continually pushing the boundaries of what can be achieved with personalized cell and gene-based therapies.

The CCI team is exploring numerous advancements in CAR T cell therapy, developing new and improved strategies to enhance the effectiveness of CAR T cells against various types of blood cancers and are increasingly focusing on adapting these therapies for solid tumors, which present a unique set of challenges due to their complex tumor microenvironments. The team's research includes engineering CAR T cells that can better navigate and penetrate these solid tumors, potentially increasing the therapy's efficacy.

Beyond cancer, June and the CCI team are exploring the potential of modified T cells to treat autoimmune diseases, infectious diseases, and other conditions where the immune system may prove a powerful weapon.