The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell-Based Cancer Immunotherapy with Genetically Modified T Cells

Gershovich, Pavel; Karabelskii, A. V.; Улитин, А. Б.; Ivanov, Roman

doi:10.1134/s0006297919070022

Cited by 6 publications

(4 citation statements)

References 89 publications

(69 reference statements)

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“…Modulation of the interleukin cocktails can affect the memory functions of T cells and are used as an alternative approach to increase the efficacy of CAR-T cell therapy ( 144 , 149 – 152 ). Cytokines are biologically active peptides that act by binding to their specific receptors located on cell surfaces ( 153 ). Interleukins are a subgroup of cytokines that allow communication between cells of the immune system; they determine processes such as the activation, differentiation, maintenance, function, and proliferation of immune cells ( 154 ).…”

Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

“…The interleukins chosen for the manufacturing process influences the T-cell proliferation and differentiation in CAR-T cell cultures ( 144 ). The most used and studied interleukin is IL-2, which has an essential role in the manufacturing process of CAR-T cells since it stimulates cell proliferation and maintains cell viability during the expansion phase ( 153 ). However, the stimulation of T cells with IL-2 favors the differentiation of short-life-span and exhausted cells because IL-2 induces a switch to glycolysis, a feature of T E cells ( 33 , 155 ).…”

Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

See 1 more Smart Citation

CAR-T Cell Performance: How to Improve Their Persistence?

López-Cantillo¹,

Urueña

Camacho³

et al. 2022

Front. Immunol.

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Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

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Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

Section: Strategies To Improve the Persistence Of Car-t Cellsmentioning

confidence: 99%

CAR-T Cell Performance: How to Improve Their Persistence?

López-Cantillo¹,

Urueña

Camacho³

et al. 2022

Front. Immunol.

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show abstract

“…The most commonly used cytokine for CAR T cell production is IL-2. However, IL-2 promotes glycolysis for rapid proliferation but leads to the formation of short-lived, highly differentiated, and exhausted CAR T cells [ 103 , 104 ]. Efforts to substitute IL-2 have focused on alternative γ-chain cytokines, including IL-7, IL-15, and IL-21.…”

Section: Strategies To Target Car T Cell Metabolismmentioning

confidence: 99%

Role of CAR T Cell Metabolism for Therapeutic Efficacy

Saborido

Völkl

Aigner

et al. 2022

Cancers

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Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred CAR T cells. T cell phenotypes that have been shown to be particularly well suited for CAR T cell therapy display certain metabolic characteristics; whereas T-stem cell memory (TSCM) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (TEFF) rely on glycolysis to support their cytotoxic function. Various parameters of CAR T cell design and manufacture co-determine the metabolic profile of the final cell product. A co-stimulatory 4-1BB domain promotes OXPHOS and formation of central memory T cells (TCM), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (TEM). Therefore, modification of CAR co-stimulation represents one of the many strategies currently being investigated for improving CAR T cells’ metabolic fitness and survivability within a hostile tumor microenvironment (TME). In this review, we will focus on the role of CAR T cell metabolism in therapeutic efficacy together with potential targets of intervention.

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“…Modulation of the interleukin cocktails can affect the memory functions of T cells and are used as an alternative approach to increase the efficacy of CAR-T cell therapy (144,(149)(150)(151)(152). Cytokines are biologically active peptides that act by binding to their specific receptors located on cell surfaces (153). Interleukins are a subgroup of cytokines that allow communication between cells of the immune system; they determine processes such as the activation, differentiation, maintenance, function, and proliferation of immune cells (154).…”

Section: Cytokines Used To Yield Undifferentiated Car-t Cellsmentioning

confidence: 99%

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The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell-Based Cancer Immunotherapy with Genetically Modified T Cells

Cited by 6 publications

References 89 publications

CAR-T Cell Performance: How to Improve Their Persistence?

CAR-T Cell Performance: How to Improve Their Persistence?

Role of CAR T Cell Metabolism for Therapeutic Efficacy

Table_1.docx

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