New details regarding how two of the most prevalent kinds of chimeric antigen receptor (CAR) T cells eradicate cancer has been revealed by a study that was published in Science Advances. Researchers from Houston Methodist Hospital, Texas Children’s Hospital, Baylor College of Medicine, Texas Children’s Cancer Center, and the Center for Cell and Gene Therapy at Baylor investigated the impact of molecular dynamics at the immune synapse, where CAR T cells attach to cancer cells, on anticancer activity.
In order to build the groundwork for creating CAR molecules that optimize antitumor activity beyond B cell malignancies, researchers set out to comprehend how CAR T cells with various signaling domains function at the molecular and cellular levels.
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,
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. Nabil Ahmed
The study team investigated molecular dynamics at the immunological synapse under the direction of first author Dr. Ahmed Gad, a postdoctoral associate in Ahmed’s lab. The team isolated the membrane lipid rafts, which are cholesterol-rich molecules on the cell surface where the majority of molecular interactions between cells occur, in order to biopsy the CAR T cell immunological synapse.
They discovered that CD28.ζ-CAR molecules move swiftly through the immunological synapse, killing cancer cells in a matter of minutes. This made it possible to master “serial killing” of cancer cells and restore CAR T cells quickly. On the other hand, scientists discovered that 4-1BB.ζ-CAR molecules remain in the immunological synapse and lipid rafts. Together, the 4-1BB.ζ-CAR T cells proliferate and kill tumor cells in a process known as “collaborative” killing.
Observing the distinct pattern of dynamics between single molecules helps us understand the big picture of how these products work,
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
Dr. Ahmed Gad
Source: Baylor College of Medicine – News
Journal Reference: Gad, Ahmed Z., et al. “Molecular Dynamics at Immune Synapse Lipid Rafts Influence the Cytolytic Behavior of CAR T Cells.” Science Advances, 2025, DOI: 10.1126/sciadv.adq8114.
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