Use of CAR-T Cell Therapy to Target Solid Tumors
CAR-T cell therapy has had success in treating children and adults with leukemia and lymphoma. However, CAR T cells have not had the same success against solid tumors.
CAR-T cell therapy has had success in treating children and adults with leukemia and lymphoma. However, CAR T cells have not had the same success against solid tumors. Now, scientists report they have uncovered a molecular mechanism that in a preclinical study unlocked the promise of CAR-T cell therapy for treatment of solid tumors. The findings are published in the journal Nature. Since the T cells represent a cornerstone for cancer immunotherapy, the identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anticancer immunotherapy. This work extends from the basic biology of T lymphocytes to a possible application in the clinic, with an exploration of deep molecular mechanisms.
Researchers identified that an interaction between the protein c-Myc and the complex cBAF early in T-cell activation influences cell fate trajectory. Memory cells stick around and can generate effector cells and they can launch continued attacks. So, memory cells likely do a better job of getting rid of tumors.
Researchers recently showed that the distribution of the protein c-Myc in a parental T cell can be important for this process. They knew that a daughter cell with more c-Myc becomes an effector cell. In this study, they found that the protein complex cBAF interacted with c-Myc. Daughter cells with high cBAF and c-Myc concentrations became effector T cells. They collaborated to confirm that targeting multiple parts of the cBAF complex affects memory T-cell generation. The discovered the exact locations in the genome where cBAF components bind and found that cBAF promoted the expression of genes associated with effector cell function.
The team of researchers used the molecular information they discovered to increase CAR T–cell efficacy. They applied a cBAF inhibitor during CAR T–cell activation to generate more memory T cells. In a preclinical model, the inhibitor-treated T cells controlled tumor growth better than untreated cells. The treated cells also survived longer and in larger numbers. cBAF factors are a potential target to boost CAR-T therapeutic effects against cancer, but this work demonstrates that by better understanding basic immunobiology and T cell function, we can develop better therapeutics for cancer and other disease.
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