Clinically-relevant T cell expansion protocols activate distinct cellular metabolic programs and phenotypes

Abstract

Ex vivo expansion conditions used to generate T cells for immunotherapy are thought to adopt metabolic phenotypes that impede therapeutic efficacy in vivo. The comparison of five different culture media used for clinical T cell expansion revealed unique optima based on different output variables including proliferation, differentiation, function, activation and mitochondrial phenotypes. T cells adapted their metabolism to match their media expansion condition as shown by glucose and glutamine uptake, and patterns of glucose isotope labeling. However, adoption of these metabolic phenotypes was uncoupled to T cell function. Furthermore, T cell products cultured in ascites from ovarian cancer patients displayed suppressed mitochondrial activity and function irrespective of the ex vivo expansion media. In one case, culturing in ascites resulted in increased glucose uptake which was insufficient to rescue T cell function. Thus, ex vivo T cell expansion conditions have profound impacts on metabolism and function.

Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy

“…Finally, T cells were expanded in the presence of phosphoinositide 3-kinase inhibitor (PI3K) to enrich for memory T cells in an ongoing BCMA CAR-T clinical trial which is reported to show promising signs of improved efficacy ( 96 ). Even the choice of media can have a major impact on the function and metabolism of the T cells ( 97 ). Work in NK cells has been carried out to examine the impact of changing feeder cells used for expansion, and how this can affect metabolic fitness and cytotoxicity ( 98 , 99 ).…”