T-Cell Dysfunction as a Limitation of Adoptive Immunotherapy: Current Concepts and Mitigation Strategies

SIMPLE SUMMARY: T cells are immune cells that can be used to target infections or cancers. Adoptive T-cell immunotherapy leverages these properties and/or confers new features to T cells through ex vivo manipulations prior to their use in patients. However, as a “living drug,” the function of these cells can be hampered by several built-in physiological constraints and external factors that limit their efficacy. Manipulating T cells ex vivo can impart dysfunctional features to T cells through repeated stimulations and expansion, but it also offers many opportunities to improve the therapeutic potential of these cells, including emerging interventions to prevent or reverse T-cell dysfunction developing ex vivo or after transfer in patients. This review outlines the various forms of T-cell dysfunction, emphasizes how it affects various types of T-cell immunotherapy approaches, and describes current and anticipated strategies to limit T-cell dysfunction. ABSTRACT: Over the last decades, cellular immunotherapy has revealed its curative potential. However, inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death, undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer, are discussed, with an emphasis on strategies used during ex vivo manipulations to limit T-cell dysfunction. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features are key to the development of improved cellular immunotherapies.