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Counteracting CAR T cell dysfunction
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DOI：10.1038/s41388-020-01501-x.png)
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Abstract
En 中文
In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an exhaustion-resistant phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.
Keywords:
ARYL-HYDROCARBON RECEPTOR
INHIBITORY RECEPTORS
4-1BB COSTIMULATION
ANTITUMOR EFFICACY
EFFECTOR FUNCTIONS
TUMOR STROMA
LIFE-SPAN
EXHAUSTION
SENESCENCE
PD-1
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