Enhanced Persistence and Potency of Hypoimmune Allogeneic CAR T Cells: Overcoming Immune Rejection and Maintaining Anti-Tumor Efficacy

The abstract discusses the development of engineered CAR T cells designed to avoid immune rejection and enhance their effectiveness. The strategy involves the use of allogeneic, rather than autologous, T cells, which can be manufactured more easily and with better quality control. The challenge addressed is the host's immune response against the allogeneic T cells, which can reduce their efficacy.

The researchers engineered immune evasive CAR T cells by leveraging hypoimmune technology, which includes the deletion of certain genes to reduce the cells' immunogenicity and the overexpression of CD47 to protect against innate immune responses. The cells were created by editing healthy donor T cells to remove HLA class I and II genes, along with other modifications to enhance their ability to evade immune detection.

The hypoimmune CAR T cells were shown to avoid recognition and activation by T cells in sensitized allogeneic humanized mice. In contrast, non-edited CAR T cells from the same donor caused significant T cell activation. The overexpression of CD47 was also found to protect the cells from NK cell and macrophage killing, both in vitro and in vivo.

Importantly, the hypoimmune CAR T cells maintained their antitumor activity against B cell leukemia models, indicating that the modifications did not compromise their therapeutic potential. The cells demonstrated effective clearance of leukemic cells in mouse models, comparable to unedited CAR T cells.

The study concludes that hypoimmune CAR T cells could offer a universal solution for CAR T cell therapy, capable of persisting in the body without the need for immunosuppression. They also suggest potential for use in sensitized patients and for re-dosing strategies, offering a promising approach to improving the durability and effectiveness of CAR T cell therapies.