A study published in Scientific advances shares new insights into how two of the most common types of chimeric antigen receptor (CAR) T cells kill cancer. 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 examined how molecular dynamics at the immune synapse (where CAR T cells bind to cancer cells) affects anticancer activity.
In this study, researchers set out to understand how CAR T cells with different signaling domains function at the molecular and cellular levels to lay the foundation for the design of CAR molecules that maximize 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 steadily over a long period of time,” said senior author Dr. Nabil Ahmed, a 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 “design CAR T cells that adapt their killing behavior to attack difficult-to-treat malignancies, such as solid tumors.” Ahmed is also a member of the Center for Cellular and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center.
Led by first author Dr. Ahmed Gad, a postdoctoral associate in Ahmed’s lab, the research team examined molecular dynamics at the immune synapse. The team biopsied the immunological synapse of CAR T cells by isolating 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 travel rapidly through the immune synapse, working within minutes to kill cancer cells. This allowed rapid recovery of CAR T cells and mastery of “serial death” of cancer cells. In contrast, the researchers found that 4-1BB.ζ-CAR molecules remain in lipid rafts and at the immune synapse. 4-1BB.ζ-CAR T cells multiply and work together, resulting in sustained “collaborative” destruction of tumor cells.
“Looking at the distinctive pattern of dynamics between individual molecules helps us understand the bigger 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.
Other authors who contributed to this work include Jessica S. Morris, Lea Godret-Miertschin, Melisa J. Montalvo, Sybrina S. Kerr, Harrison Berger, Jessica CH 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, Dan L Duncan Comprehensive Cancer Center, University of Houston, and University of Virginia.
This work was supported by the National Institutes of Health Moonshot U54 Grant, National Cancer Institute, Texas Cancer Prevention and Research Institute, Be Brooks Brave Fund St. Baldrick Foundation Grant, Stand Up To Cancer , St. Baldrick’s Pediatric Cancer Dream Team Translational Research Grant, Triumph Over Kids Cancer Foundation, Alex Moll Family Fund and The Faris Foundation.