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Pushing T cells down memory lane may improve cancer therapy

Scientists at St. Jude Children’s Research Hospital identified a molecular mechanism that in a preclinical study unlocked the promise of CAR Tcell therapy for treatment of solid tumors. The results were published today in the journal Nature.

“Our work extends from the basic biology of T lymphocytes to a possible application in the clinic, with an exploration of deep molecular mechanisms along the way,” said co-corresponding author Doug Green, Ph.D., St. Jude Department of Immunology chair. “We found that just like many of us, if you are an activated T cell, things that happen early in your life can impact your later development. We identified that an interaction between the protein c-Myc and the complex cBAF early in T-cell activation influences cell fate trajectory.”

Chimeric antigen receptor (CAR) T cells are a type of immunotherapy that modifies a patient’s immune cells to target cancer cells. This type of therapy has had remarkable success in treating children and adults with leukemia and lymphoma, particularly in relapsed patients. However, CAR T cells have not had the same success against solid tumors, with problems involving persistence and function.

Currently too many CAR T cells become effector cells, those that directly kill infected or cancerous cells. Too few become memory cells that persist and create more T cells over the long term. The researchers believed that if they created more memory cells, they could improve CAR Tcell therapy.

“Effector cells do a job and then die,” Green said. “Memory cells stick around and can generate effector cells (while maintaining the memory cell pool) and therefore they can launch continued attacks. So, we think that memory cells likely do a better job of getting rid of tumors.”

A molecular mystery

The researchers needed to find what guides T cells to become effector or memory types and then use that knowledge to modify the process. The process begins when a T cell is activated by an antigen, such as a piece of virus or cancer-related molecule. That parental T cell divides into two daughter cells, which can become effector or memory cells.

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