Metabolic modulation of T cells increases early memory phenotype and improves T function for effective CAR-T cell therapy

Background & Aim Chimeric antigen receptor (CAR)-T cell therapy represents an incredibly promising cellular immunotherapy due to broad applicability to most patients, ability to circumvent “tumor escape,” and the ability to rapidly deliver a population of tumor specific T cells. Despite the impressive initial response rates in leukemia and lymphoma patients treated with the FDA approved CAR-T therapy, not all patients respond to CAR-T cell therapy. A pre-requisite for the success of cell therapy is the in vivo persistence of CAR modified T cells following adoptive transfer. Studies indicate that the in vivo proliferating CAR-T cells from patients responding to treatment show increased early and central memory surface markers whereas T cells from non-responders upregulate genes associated with effector differentiation, glycolysis, exhaustion and apoptosis. It is well known that after activation the metabolic and biosynthetic demands of T cells dramatically increase to support growth, proliferation, and effector function. We have effectively applied this knowledge towards the development of a new T cell expansion medium (NextGen OpTmizer) for CAR-T drug manufacturing. Methods, Results & Conclusion NextGen OpTmizer is an extension of our existing CTS™ OpTmizer™ T Cell Expansion medium. The results show that NextGen OpTmizer increases T cell expansion, retains a more favorable central memory phenotype, while suppressing differentiation into terminal effector T cell phenotype. Further, T cells generated by NextGen OpTmizer also retains their ability to produce inflammatory cytokines in vitro. NextGen OpTmizer is also capable of expanding T cells in different culture vessels such as static vessels, static culture bags and Hyperforma Rocker platform. Collectively, these feasibility data from NextGen OpTmizer is the first step towards the development of a T-cell expansion medium, which can convert non-responder T cells to responder T cells thus leading to an effective CAR-T cell therapy.