Scientists from St. Jude create more effective CAR immunotherapies using a molecular anchor

Adding a molecular anchor to the key protein that recognizes cancer in cellular immunotherapies could make treatments significantly more effective. The scientists from Saint Jude Children’s Research Hospital found that immune cells with an anchor protein increased cancer destruction regardless of the type of cancer cell or form of cancer it targeted. The molecular anchor concept is a novel design to improve chimeric antigen receptor (CAR)-based immunotherapies. CARs have shown some promise in the clinic, but have not yet achieved widespread success across tumor types. The findings were published today in Natural Biotechnologies.

“We’ve come up with a new way to more efficiently and effectively bind to and target cancer cells,” said first and corresponding author Peter Chockley, Ph.D., Saint Jude Department of Bone Marrow Transplantation and Cell Therapy. “The design of an anchor domain is modular and versatile. We have shown that it works on multiple CARs and multiple immune cell types – including natural killer (NK) and T cells.”

Scientists can reprogram human immune cells to target cancer cells by adding engineered CAR proteins to their surface. CAR T cells have shown some success in the clinic for some cancers, such as relapsed leukemia. However, CAR T cells have not been able to achieve such success in solid tumors, in part because of problems with immune cell activation. The Saint Jude group discovered a way to “anchor” the CAR molecule to immune cells, allowing the cells to activate more easily and kill cancer more effectively than conventional CARs. Anchored CARs increase survival in animal models of multiple tumor types, including lung, bone, and brain cancers.

“Discovery of an anchor domain can easily be translated into an early phase clinical trial,” said senior author Stephen Gottschalk, MD, Saint Jude Department of Bone Marrow Transplantation and Cell Therapy. “It doesn’t require any other new technology. We strongly believe that this approach should be tested in the clinic because no one has tried it before and it looks very promising in our preclinical work.

Carefully structured CARs kill cancers better

CARs are a key molecule in the process of killing cancer. The outside of the molecule recognizes a protein in the cancer cell. This forms a complex of molecules and proteins between the two cells called an immune synapse. Once the immune synapse is formed, the part of the CAR inside the immune cell receives signals from the parts outside the cell. These interactions send a signal to activate and kill the cancer cell, but these complex communications can be difficult for conventional CAR T and NK cells to interpret.

“Our approach is different because it focuses on the organization,” Chokley said. “CAR immune cells form synapses that are very disorganized. The anchoring domain we added organizes internal scaffolding proteins and makes a better synapse and then introduces other existing signaling proteins. Simply adding organization improves the cars dramatically.”

Imagine the back of a desktop computer with lots of tangled cables. Enabling CAR requires untangling cables and cords to add a monitor. If the cables are unorganized, it can be incredibly difficult. If one has organized the cables well, a task that might have taken hours becomes easy. Conventional CARs develop a disorganized immune synapse like a desk covered in a mess of cables, causing delayed signaling in cells. By adding an anchoring domain to the underside of the CAR, the scientists organized the CARs—the molecular equivalent of adding cable ties to organize computer cables.

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