Strategies to enhance CAR-T persistence

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development.

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…ATPIF1 knockdown in allogeneic CD19 CAR‐Ts increases the glycolytic activity to compensate for mitochondrial defects while decreasing the ability of these cells to generate ATP via other energy substrates, such as fatty acids or amino acids, which inhibits CD8+ Tm formation and virulence factor production and accelerates CD8+ Teff exhaustion 159 . In summary, both the glycolysis inhibitor 2‐DG and selective PI3K inhibitors may contribute to an increased Tcm/Tem ratio and limit CAR‐T glycolytic activity to maintain persistent stemness 160,161,193 . Notably, activation of the TGF‐β/Smad signalling pathway in the hypoxic TME tends to reduce T‐cell glycolytic competitiveness 194 ; therefore, the knockdown of TGF‐βR2 in CAR‐Ts inhibits TGF‐β signalling to facilitate CAR‐T survival in vivo and increase the tumour elimination efficacy 195–197 .…”

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

“…While the metabolic consequences of such modifications have not been fully explored, they have been implemented to improve CAR T entry into and function within the TME. While first-generation CARs had a single CD3ζ signaling domain they were ultimately not very effective ( 89 – 91 ). Second and third generation CAR T cells have incorporated one or two costimulatory signals, respectively.…”

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

“…It has become clear that robust expansion and long-term persistence of CAR-T cells are key elements in achieving complete and durable responses. The persistence, however, of functional CAR-Ts is hampered by several factors, including T-cell exhaustion, differentiation, prolonged antigen stimulation, rejection of immunogenic CARs by the host-immune system, contraction when antigen concentration is insufficient to drive T-cell proliferation, activation-induced cell death, or replicative senescence [ 11 , 12 , 13 ] and many efforts have been made towards increasing the persistence of T-cell therapy products in vivo [ 14 , 15 , 16 , 17 ]. In this review, we outline the main characteristics of epigenetic regulation and describe the epigenetic modifications that drive T-cell persistence, with emphasis on those underlying T-cell exhaustion, differentiation, and infiltration.…”