A recent study published in Science Advances provides insights into the mechanisms of two prevalent types of chimeric antigen receptor (CAR) T cells and their cancer-killing capabilities. Researchers from Baylor College of Medicine, Texas Children’s Cancer Center, and the Center for Cell and Gene Therapy at Baylor, Houston Methodist Hospital, and Texas Children’s Hospital explored how molecular dynamics at the immune synapse—the site where CAR T cells attach to cancer cells—influence anticancer activity.
The goal was to understand how CAR T cells with varying signaling domains function at molecular and cellular levels. This understanding aims to enhance the design of CAR molecules for improved antitumor activity beyond B cell malignancies.
“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 Dr. Nabil Ahmed, senior author and professor of pediatrics – hematology and oncology at Baylor and Texas Children’s.
Dr. Ahmed Gad led the research team in examining molecular dynamics at the immune synapse by isolating membrane lipid rafts—cholesterol-rich molecules on the cell surface crucial for cellular interactions.
The study found that CD28.ζ-CAR molecules move rapidly through the immune synapse, allowing quick cancer cell destruction and enabling rapid recovery for subsequent attacks on cancer cells. Conversely, 4-1BB.ζ-CAR molecules linger in these lipid rafts, facilitating sustained collaborative killing as they multiply and work together against tumor cells.
“Observing the distinct pattern of dynamics between single molecules helps us understand the big picture of how these products work,” Gad stated.
“Tumors are very sophisticated. We need to adapt our tools to the biology of the disease,” Ahmed added.
Contributors to this research 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 among others affiliated with institutions such as Baylor College of Medicine and Texas Children’s Hospital.
Funding support came from various organizations including the National Institutes of Health U54 Moonshot Grant and Stand Up To Cancer.
