Researchers led by Baylor College of Medicine have discovered key differences in the cancer-fighting behaviors of CAR T cells, unveiling the potential to engineer more effective treatments for challenging cancer types.
A new study published in Science Advances unveils significant findings about the cancer-killing behavior of two types of chimeric antigen receptor (CAR) T cells. Scientists from Baylor College of Medicine, alongside collaborators from Texas Children’s Cancer Center and other institutions, have uncovered the distinct molecular dynamics that occur when these immune cells engage cancer cells.
The study dives into the immune synapse, the critical zone where CAR T cells bind with their cancer targets. By exploring how molecular interactions in this zone affect antitumor activity, the researchers aim to refine CAR T cell designs for more effective cancer treatment, particularly against hard-to-treat solid tumors.
“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,” senior author Nabil Ahmed, M.D., a professor of pediatrics – hematology and oncology at Baylor and Texas Children’s, said in a news release. “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.”
Led by Ahmed Gad, the study’s first author and postdoctoral associate in Ahmed’s lab, the team focused on isolating the membrane lipid rafts — cholesterol-rich cell surface regions where crucial molecular interactions occur — to study the dynamics of CAR T cells.
The findings revealed that CD28.ζ-CAR molecules transit swiftly through the synapse, enabling rapid, successive killing of cancer cells, whereas 4-1BB.ζ-CAR molecules linger and foster a more sustained, cooperative killing approach.
“Observing the distinct pattern of dynamics between single molecules helps us understand the big picture of how these products work,” Gad said in the press release. “Next, we are studying how to dynamically adapt these CAR T cells at the synapse level to make them more effective.”
These insights pave the way for engineering CAR T cells that could adapt their behavior to combat various types of cancer, particularly solid tumors that have been notoriously challenging to treat.
“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.
By enhancing the understanding of CAR T cell molecular dynamics, this research holds promise for revolutionizing cancer treatment strategies, potentially offering new hope for patients facing malignancies that were previously elusive to conventional therapies.