A recent study published in Science Advances has shed light on the cancer-killing mechanisms of two prevalent types of chimeric antigen receptor (CAR) T cells. 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 have explored how molecular dynamics at the immune synapse—where CAR T cells attach to cancer cells—impact anticancer activity.
The research focused on understanding how CAR T cells with various signaling domains function at molecular and cellular levels. This understanding aims to aid in designing CAR molecules that enhance 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 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.
Dr. Ahmed Gad led the research team as a postdoctoral associate in Dr. Ahmed's lab. They studied molecular dynamics by isolating membrane lipid rafts—cholesterol-rich molecules on cell surfaces where most molecular interactions occur.
The findings revealed that CD28.ζ-CAR molecules quickly shuttle through the immune synapse, enabling rapid cancer cell killing and efficient recovery for subsequent attacks—a process termed "serial killing." In contrast, 4-1BB.ζ-CAR molecules linger longer within lipid rafts and the immune synapse, promoting sustained "collaborative" tumor cell destruction through multiplication and cooperation among 4-1BB.ζ-CAR T cells.
“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.
The study was conducted with contributions from 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 Malini Mukherjee affiliated with institutions including Baylor College of Medicine Texas Children’s Hospital Center for Cell Gene Therapy Dan L Duncan Comprehensive Cancer Center University Houston University Virginia
Funding support came from sources such as National Institutes Health U54 Moonshot Grant National Cancer Institute Cancer Prevention Research Institute Texas Be Brooks Brave Fund St Baldrick Foundation Fellowship Stand Up To Cancer St Baldrick Pediatric Cancer Dream Team Translational Research Grant Triumph Over Kids Cancer Foundation Alex Moll Family Fund Faris Foundation Full list funding details available publication
