NEW OBSERVATIONS MAY LEAD TO MORE EFFECTIVE CAR-T CELL THERAPIES

CAR-T cell therapy is the most effective for lymphoma treatment with up to 90% of patients responding to this therapy. However, the cost of CAR-T cell manufacture and side effects are still so high that most of patients can’t afford. In a recent nature paper, Fraietta et al (2018) has revealed a phenomena that may lead to reduction of CAR-T cell manufacture cost and side effect. When treating a patient with CAR-T cells, Fraietta noticed that patient’s tumors got remission after two months of second dose, which is a month longer than that achieved in typical patients treated with CAR-T cells. To understand why this patient take too long to respond to the therapy, researchers first examined the CAR-T cell population in this patient’s blood. They were surprise when found out that most, if not all, of the CAR-T cells are central memory cells originating from a single cells. They, then, profiled genome landscape of these CAR-T cells and discovered that the CAR-T constructs are inserted into a TET2 locus while the other is mutated, leading to inactivation of the TET2 gene. The TET2 gene inactivation in T cells has been shown to lock T cells into T central memory cells. To confirm the in vivo observation, the researchers knocked out TET2 gene in human T cells, and as expected, all of these human T cells differentiated into T central memory cells, preventing them from entering a dysfunction mode called exhaustion. It, therefore, requires only several thousand CAR-T cells for infusion instead of several hundred million cells as current doses. In addition, these T central memory cells also secrete less cytokines than typical CAR-T cells, which may lead to reduce side effects of the CAR-T cell therapies. Even though more researches need to be done to bring this new observation to practices, this study opened a new hope for cancer patients.

Implication: A factor need to be considered when licensed CAR-T cell therapies.

Reference: https://www.nature.com/articles/d41586-018-05251-5 .

Hoang Quoc Chinh, PhD