CAR T-cell therapy is an approach to cancer treatment that involves taking a type of immune cell called T-cells from a patient and engineering them to be better at battling the disease and sometimes growing more of them, then returning them to the patient. While there can be problems with the method, there have been success stories, and in the future, it may be an excellent way to treat many people that have cancer. Scientists are still working on improving CAR T-cell therapy through clinical trials and research.
Reporting in Nature, investigators at the St. Jude Children's Research Hospital have found a way to make CAR T-cell therapy more effective. In a mouse model of cancer, they were able to slow the growth of tumors and extend the life of the animals.
"The goal has been to increase the persistence of tumor-specific T-cells and their anti-tumor efficacy," said the corresponding author of the report Hongbo Chi, Ph.D., a member of the St. Jude Department of Immunology. "This study offers a way to accomplish both simultaneously by reprogramming tumor-specific T cells to have better persistence like long-lived naïve or memory T-cells and exhibit robust killing activity like functionally competent effector T-cells."
The researchers applied the CRISPR/Cas9 gene-editing tool to target an enzyme called REGNASE-1 that can act as a brake on the anti-tumor response. After the enzyme was removed, the engineered T-cells were more effective at attacking cancerous tumors, there were more T-cells at work, and they stuck around longer in the mice. In models of leukemia and melanoma, this approach allowed the mice to live longer, and reduced tumor size compared to mice treated with T-cells in which REGNASE-1 was still active.
The researchers also found two other molecules called PTPN2 and SOCS1 that are involved in T-cell activity. If they were removed using CRISPR/Cas9 along with REGNASE-1, the T-cell therapy worked even better.
"This research showed REGNASE-1 also inhibits two important T cell signaling pathways," said co-first study author Jun Wei, Ph.D., a St. Jude staff scientist. Wei also determined that two molecules that can control gene expression, transcription factors called BATF and TCF-1, are impacted by REGNASE-1. BATF is involved in metabolism in T-cells and TCF-1 promotes longevity in the cells.
"Conventional wisdom held that these processes were reciprocal and that increasing the anti-tumor activity of T-cells meant T-cell longevity suffered. We showed that is not necessarily the case," Wei added.
"Combination therapy is key to the clinical success of cancer immunotherapy. We wanted to provide additional insights into the clinical potential of the finding," Wei said.
"We are excited to move this forward and explore possibly targeting REGNASE-1 for cancer therapy," noted Chi.