A groundbreaking study from Baylor College of Medicine explores how two types of CAR T cells target cancer, shedding light on their distinct killing mechanisms.
A new study published today (January 10) in Science Advances reveals new insights into how two common types of chimeric antigen receptor (CAR) T cells target and destroy cancer. Researchers from Baylor College of Medicine, Texas Children’s Cancer Center, and the Center for Cell and Gene Therapy, in collaboration with Houston Methodist Hospital and Texas Children’s Hospital, investigated the molecular dynamics at the immune synapse—the critical site where CAR T cells bind to cancer cells.
The study aimed to uncover how CAR T cells with distinct signaling domains operate at the molecular and cellular levels. This knowledge could guide the development of CAR T cell therapies designed to enhance their effectiveness, particularly against hard-to-treat cancers beyond B cell malignancies.
The Sprint vs. Marathon Analogy in CAR T Cells
“We looked at two different types of CAR T cells. The first, CD28.ζ-CART cells, are like sprinters. They kill cancer cells quickly and efficiently, but their activity is short-lived. The second, 4-1BB.ζ-CART cells, are like marathon runners. They kill cancer cells consistently over a long period,” said senior author Dr. Nabil Ahmed, professor of pediatrics – hematology and oncology at Baylor and Texas Children’s. “We need to understand what’s happening at the molecular level so we can engineer CAR T cells to adapt their killing behavior to target hard-to-treat malignancies, such as solid tumors.” Ahmed also is a member of the Center for Cell and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center.
Investigating Molecular Dynamics at the Immune Synapse
Led by first author Dr. Ahmed Gad, postdoctoral associate in Ahmed’s lab, the research team examined molecular dynamics at the immune synapse. The team biopsied the CAR T cell immunological synapse by isolating the membrane lipid rafts – cholesterol-rich molecules on the cell surface where most molecular interactions between cells take place.
They found that CD28.ζ-CAR molecules shuttle through the immune synapse quickly, working within minutes to kill cancer cells. This enabled fast CAR T cell recovery and a mastery of “serial killing” of cancer cells. In contrast, researchers found that 4-1BB.ζ-CAR molecules linger in the lipid rafts and immune synapse. The 4-1BB.ζ-CAR T cells multiply and work together, resulting in sustained “collaborative” killing of tumor cells.
Adapting CAR T Cells for Hard-to-Treat Tumors
“Observing the distinct pattern of dynamics between single molecules helps us understand the big picture of how these products work,” Gad said. “Next, we are studying how to dynamically adapt these CAR T cells at the synapse level to make them more effective.”
“Tumors are very sophisticated. We need to adapt our tools to the biology of the disease. This may involve using multiple tools that work in different ways at different stages,” Ahmed added.
Reference: “Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells” by Ahmed Z. Gad, Jessica S. Morris, Lea Godret-Miertschin, Melisa J. Montalvo, Sybrina S. Kerr, Harrison Berger, Jessica C. H. Lee, Amr M. Saadeldin, Mohammad H. Abu-Arja, Shuo Xu, Spyridoula Vasileiou, Rebecca M. Brock, Kristen Fousek, Mohamed F. Sheha, Madhuwanti Srinivasan, Yongshuai Li, Arash Saeedi, Kandice R. Levental, Ann M. Leen, Maksim Mamonkin, Alexandre Carisey, Navin Varadarajan, Meenakshi Hegde, Sujith K. Joseph, Ilya Levental, Malini Mukherjee and Nabil Ahmed, 10 January 2025, Science Advances.
DOI: 10.1126/sciadv.adq8114
Other authors who contributed to this work 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. They are affiliated with one or more of the following institutions: 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 work was supported by 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. See the publication for a full list of funding details.
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