CAR-T Pioneer Carl June Reports Durable Persistence of CAR-T Cells Over a Decade Post-Treatment

In May, the “2023 Sequoia Global Healthcare Industry Summit” was held at the Zhangjiang Science Hall in Shanghai. Themed “End-in-Mind, Going Far by Attending to the Minute,” the summit featured keynote presentations ranging from scientific breakthroughs in cutting-edge healthcare to concrete application scenarios and solutions for translating technological advances into practice. It systematically dissected “unmet needs” in the healthcare sector, covering a broad spectrum of hot topics of common interest to academia, industry, and investment communities, thereby fostering effective and in-depth exchanges.

On the second day of the conference, Carl June, known as the “Father of CAR-T,” a member of the U.S. National Academy of Sciences, and a tenured professor at the University of Pennsylvania, delivered an online keynote address titled “New Trends in the Global Cell Therapy Field,” sharing insights into the development trends and latest research advances in CAR-T therapy. VCBeat New Medicine has compiled and edited the highlights of his presentation.

CAR-T therapy, or Chimeric Antigen Receptor T-Cell Immunotherapy, is primarily used for the precise targeted treatment of malignant hematologic diseases and solid tumors. T cells, also known as T lymphocytes, play a crucial role in immune responses by defending against infections, tumors, and foreign substances.

In CAR-T cell therapy, technicians extract T cells from the patient’s peripheral blood, engineer them to express chimeric antigen receptors (CARs) to generate CAR-T cells, and then infuse these modified cells back into the patient. Leveraging the CAR as a “targeting and navigation system,” CAR-T cells precisely recognize tumor cells in the body and release a large amount of effector molecules through immune-mediated mechanisms, thereby achieving highly efficient tumor eradication.

The first CAR-T therapy products to reach the market were Novartis’s Kymriah (2017) and Gilead Sciences’ Yescarta (2017). Today, CAR-T therapy is highly prominent worldwide, with hundreds of companies developing autologous CAR-T cells, natural killer cells, macrophages, γδ T cells, allogeneic CARs, and T-cell receptor-engineered T cells. As of May 2023, there were nearly 900 CAR-T cell clinical trials registered on ClinicalTrials.gov, the majority of which were conducted in China.

In 2010, a patient with chronic lymphocytic leukemia received Kymriah at the University of Pennsylvania. He was the first patient worldwide to undergo CAR-T therapy and has remained cancer-free for over a decade. Subsequently, Carl June’s team treated numerous adult patients with B-cell malignancies using CAR-T therapy, and in 2012, the team began applying CAR-T therapy to treat pediatric acute lymphoblastic leukemia.

More than a decade has passed since the first cohort of patients received CAR-T cell therapy in 2010. The team led by Carl June conducted follow-up studies on these patients and published their latest research findings in Nature in 2022.

Study results show that, to date, cancer has not recurred in these patients following CAR-T therapy.Moreover, more than a decade later, both CD4+ and CD8+ CAR-T cells persist in the patient’s body.

Both CD4+ T cells and CD8+ T cells are essential components of cell-mediated immunity. CD4+ T cells exert helper immune functions by producing cytokines that stimulate other immune cells to enhance their activity, whereas CD8+ T cells are responsible for eliminating infected, damaged, and tumor cells.

Studies have also shown that the types and quantities of CAR-T cells infused into patients change over time. In the early stages of treatment, CD8+ CAR-T cells are more abundant, facilitating the precise killing of cancer cells; whereas several years later, CD4+ CAR-T cells become predominantly prevalent, contributing to long-term disease control.

As CAR-T cell technology gradually matures, the composition of CAR structures continues to evolve. First-generation CAR-T cells exhibit low proliferative capacity and reduced cytotoxicity, eliciting only transient T-cell responses and failing to induce durable tumor remission.To overcome this limitation, second-generation CAR constructs are additionally equipped with co-stimulatory domains, such as 4-1BB and CD28.

In previous studies, Carl June’s team found that 4-1BB can induce sustained proliferation of human T cells. This follow-up study demonstrates that incorporating 4-1BB into the CAR-T cell construct improves the persistence of CAR-T cells in patients with hematologic malignancies and enhances memory formation.

Cytokine Release Syndrome is a common side effect of CAR-T cell therapy. While CAR-T cells attack tumor cells, they release large amounts of cytokines that promote inflammatory responses to “recruit” additional immune cells to eliminate the tumor. However, excessive cytokine levels can disrupt the body’s immune balance, causing damage to normal organs and tissues.

In 2012, when Carl June’s team treated the first pediatric patient, Emily, with CAR-T therapy, she developed severe cytokine release syndrome (CRS). Tocilizumab had previously been indicated only for autoimmune arthritis; Carl June’s team serendipitously administered it to Emily. Not only was her CRS controlled, but her acute lymphoblastic leukemia was also cured by the CAR-T therapy. Currently, tocilizumab has received FDA approval for the treatment of CRS induced by CAR-T therapy.

Carl June’s team has been applying CAR-T therapy for over a decade, and the FDA has currently approved six drugs targeting CD19 and B-cell maturation antigen (BCMA). To date, more than 15,000 patients worldwide have received CAR-T therapy, with autologous CAR-T therapy demonstrating an excellent safety record. However, the safety profiles of allogeneic CAR-T cells, CAR-T cells in early-stage clinical trials, and natural killer (NK) cell-based CAR-T therapies remain to be further evaluated.

Finally, Carl June stated that, in addition to its use in treating leukemia and lymphoma, CAR-T therapy has other therapeutic applications.

1: Chronic Infection (AIDS)

James Riley of the University of Pennsylvania has recently used gene-edited cells to treat patients with AIDS.

2. Autoimmune Diseases

In 2022, researchers from Ireland and Germany published a paper in *Nature Medicine* reporting that five patients with refractory lupus erythematosus achieved drug-free remission in some cases after receiving CAR-T therapy.

3. Myocardial Injury

In many chronic heart diseases, activated cardiac fibroblasts secrete excessive extracellular matrix proteins, ultimately leading to myocardial fibrosis. Scholars at the University of Pennsylvania published articles in Science and Nature, proposing that CAR-T therapy can eliminate activated cardiac fibroblasts, thereby treating myocardial injury.