Abstract Text: Chimeric antigen receptor (CAR) T cell research has exploded over the last decade. Great strides have been made in optimizing CAR T therapy for several cancers, with much focus being placed on understanding the inhospitable tumor microenvironment, in the hopes of being able to produce CARs that maintain their functionality despite factors such as poor access to nutrients and low oxygen levels.
Cell culture usually takes place at 21% O2. It has been reported that this is not optimal for culture and production of T cells, due in part to their overproduction of reactive oxygen species in response to high oxygen tension. In situ, T cells are never exposed to oxygen levels greater than 14% and often function at substantially lower levels.
CAR T cells are often expanded for up to two weeks before being administered. Prolonged exposure to 21% O2 and the corresponding overproduction of reactive oxygen species may abrogate their function and survival in vivo.
Using in vitro methods including repeated exposure to stimulus and assessment of mitochondrial fitness, we demonstrate that CD19-targeted CAR T cells can be produced in significantly lower oxygen tensions and retain their functionality, without appearing more exhausted than their counterparts produced at 21% O2.
This project aims to highlight the impact of oxygen exposure during production as a possible reason for the lack of significant progress in treating solid tumors and other tumor diseases, such as chronic lymphocytic leukemia, that create inhospitable environmental pockets where CAR T cell function might be negatively impacted.
