A recent study featured in Science Advances provides fresh perspectives on the mechanisms by which two prevalent varieties of chimeric antigen receptor (CAR) T cells eliminate cancer. Research teams from Baylor College of Medicine, Texas Children’s Cancer Center, and the Center for Cell and Gene Therapy at Baylor, along with Houston Methodist Hospital and Texas Children’s Hospital, investigated how molecular behaviors at the immune synapse, the junction where CAR T cells connect with cancer cells, influence cancer-fighting effectiveness.
The researchers aimed to uncover the molecular and cellular functionalities of CAR T cells with various signaling domains. The goal was to lay groundwork for creating CAR molecules that enhance antitumor efficacy not just for B cell cancers but for other cancer types as well.
According to Dr. Nabil Ahmed, senior author and professor of pediatrics specializing in hematology and oncology at Baylor and Texas Children’s, “We analyzed two distinct types of CAR T cells. The CD28.ζ-CART cells act like sprinters; they rapidly and effectively destroy cancer cells, but their impact is short-lived. In contrast, 4-1BB.ζ-CART cells resemble marathon runners; they consistently eliminate cancer cells over an extended period. Understanding the molecular processes involved will help in engineering CAR T cells that can adjust their killing strategies for tougher cancers, including solid tumors.” Dr. Ahmed is also part of the Center for Cell and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center.
Led by Dr. Ahmed Gad, the first author and postdoctoral associate in Dr. Ahmed’s lab, the research team focused on the molecular dynamics taking place at the immune synapse. They isolated membrane lipid rafts—cholesterol-rich structures on the cell surface crucial for molecular interactions among cells—to investigate CAR T cell behaviors.
The findings revealed that the CD28.ζ-CAR molecules traverse the immune synapse rapidly, initiating cancer cell destruction within minutes. This quick action allowed for fast recovery of CAR T cells and effective “serial killing” of cancer cells. Conversely, the 4-1BB.ζ-CAR molecules were found to persist in the lipid rafts and immune synapse. This leads to the multiplication and collaboration of 4-1BB.ζ-CAR T cells, resulting in prolonged “collaborative” destruction of tumor cells.
Dr. Gad noted, “By observing the unique movement patterns between individual molecules, we gain insights into the broader mechanism of how these therapies function. Our next step is to explore how we can dynamically modify these CAR T cells at the synapse level to enhance their effectiveness.”
Dr. Ahmed emphasized the sophistication of tumors, stating, “We need to tailor our tools to the biology of the disease, which might involve employing multiple strategies that operate differently at various stages.”
Additional contributors to this study include Jessica S. Morris, Lea Godret-Miertschin, Melisa J. Montalvo, Sybrina S. Kerr, Harrison Berger, Jessica C.H. Lee, Amr M. Saadeldin, Mohammad Abu-Arja, Shuo Xu, Spyridoula Vasileiou, Rebecca M. Brock, Kristen Fousek, Mohamed F. Sheha, Madhuwanti Srinivasan, Yongshuai Li, Arash Saeedi, Kandice Levental, Ann M. Leen, Maksim Mamonkin, Alexandre Carisey, Navin Varadarajan, Meenakshi Hegde, Sujith K. Joseph, Ilya Levental, and Malini Mukherjee. Many are affiliated with institutions such as Baylor College of Medicine, Texas Children’s Hospital, Center for Cell and Gene Therapy, the Dan L Duncan Comprehensive Cancer Center, the University of Houston, and the University of Virginia.
This study was funded by several entities, including the National Institutes of Health U54 Moonshot Grant, the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, the Be Brooks Brave Fund St. Baldrick’s Foundation Fellowship, Stand Up To Cancer, the St. Baldrick’s Pediatric Cancer Dream Team Translational Research Grant, Triumph Over Kids Cancer Foundation, the Alex Moll Family Fund, and The Faris Foundation.
