Immunotherapeutic Potential of T Memory Stem Cells

Li, Yujie; Wu, Dengqiang; Yang, Xuejia; Zhou, Sufang

doi:10.3389/fonc.2021.723888

Cited by 24 publications

(36 citation statements)

References 165 publications

(195 reference statements)

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“…Additionally, T SCM is the precursor of memory cells and presents naïve‐like biomarkers (CCR7, CD27, CD127 and CD62L). T SCM has enhanced self‐renewal and proliferation capabilities, and has a multipotent developmental potential to generate multiple subsets of memory cells 18, 19 . The memory T cell mentioned in this article mainly refers to T CM .…”

Section: The Variable Metabolic Demands Throughout T Cell Differentia...mentioning

confidence: 99%

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Metabolic plasticity and regulation of T cell exhaustion

Liu

Zhang

et al. 2022

Immunology

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The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that induces epigenetic modifications, contributing to regulating T cell differentiation. Persistent pathogen infection leads to T cell exhaustion, which is composed of two main subsets and with distinct metabolic characteristics. The progenitor exhausted T cells utilize mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) for energy, while terminally exhausted T cells mainly rely on glycolytic metabolism with impaired glycolysis and OXPHOS. Here, we compiled the latest research on how T cell metabolism defines differentiation, focusing on T cell exhaustion during chronic infections. In addition, metabolicrelated factors including antigen stimulation signals strength, cytokines and epigenetics affecting T cell exhaustion were also reviewed. Furthermore, the intervention strategies on metabolism and epigenetics to reverse T cell exhaustion were discussed in detail, which may contribute to achieving the goal of prevention and treatment of T cell exhaustion.

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Section: The Variable Metabolic Demands Throughout T Cell Differentia...mentioning

confidence: 99%

“…T SCM has enhanced self-renewal and proliferation capabilities, and has a multipotent developmental potential to generate multiple subsets of memory cells. 18,19 The memory T cell mentioned in this article mainly refers to T CM .…”

Section: The Variable Metabolic Demands Throughout T Cell Differentia...mentioning

confidence: 99%

Metabolic plasticity and regulation of T cell exhaustion

Liu

Zhang

et al. 2022

Immunology

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“…The T SCM subset has been identified in mice ( 15 ), non-human primates ( 16 , 17 ), and humans ( 18 , 19 ). In humans, approximately 2-4% of peripheral blood T cells consist of T SCM cells ( 20 ). The T SCM cells are phenotypically defined as naïve T (T N ) cells by the expression of T N cell markers, such as CD45RA, CD62L and CCR7, but are distinguishable from T N cells by two memory T cell markers: CD95 and CD122.…”

Section: Introductionmentioning

confidence: 99%

Efficient derivation of chimeric-antigen receptor-modified TSCM cells

et al. 2022

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Chimeric-antigen receptor (CAR) T-cell immunotherapy employs autologous-T cells modified with an antigen-specific CAR. Current CAR-T manufacturing processes tend to yield products dominated by effector T cells and relatively small proportions of long-lived memory T cells. Those few cells are a so-called stem cell memory T (TSCM) subset, which express naïve T-cell markers and are capable of self-renewal and oligopotent differentiation into effector phenotypes. Increasing the proportion of this subset may lead to more effective therapies by improving CAR-T persistence; however, there is currently no standardized protocol for the effective generation of CAR-TSCM cells. Here we present a simplified protocol enabling efficient derivation of gene-modified TSCM cells: Stimulation of naïve CD8+ T cells with only soluble anti-CD3 antibody and culture with IL-7 and IL-15 was sufficient for derivation of CD8+ T cells harboring TSCM phenotypes and oligopotent capabilities. These in-vitro expanded TSCM cells were engineered with CARs targeting the HIV-1 envelope protein as well as the CD19 molecule and demonstrated effector activity both in vitro and in a xenograft mouse model. This simple protocol for the derivation of CAR-TSCM cells may facilitate improved adoptive immunotherapy.

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“…We designed a combined panel of surface memory/exhaustion markers such as CD62L, CD45RO, CCR7, and PD-1 and the transcription factor TCF1. We observed that the culture conditions favored the expression of cells with a central memory phenotype (Tcm and CD62L+/CD45RO+), which are the best candidates for a sustained in vivo response ( 52 ). In addition, the cells that expanded with our culturing conditions sustained the expression of TCF1 and CCR7, thereby facilitating the maintenance of a stem cell-like state.…”

Section: Discussionmentioning

confidence: 99%

Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products

et al. 2022

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Cellular immunotherapies based on T cell receptor (TCR) transfer are promising approaches for the treatment of cancer and chronic viral infections. The discovery of novel receptors is expanding considerably; however, the clinical development of TCR-T cell therapies still lags. Here we provide a pipeline for process development and clinical-scale manufacturing of TCR-T cells in academia. We utilized two TCRs specific for hepatitis C virus (HCV) as models because of their marked differences in avidity and functional profile in TCR-redirected cells. With our clinical-scale pipeline, we reproduced the functional profile associated with each TCR. Moreover, the two TCR-T cell products demonstrated similar yield, purity, transduction efficiency as well as phenotype. The TCR-T cell products had a highly reproducible yield of over 1.4 × 109 cells, with an average viability of 93%; 97.8–99% of cells were CD3+, of which 47.66 ± 2.02% were CD8+ T cells; the phenotype was markedly associated with central memory (CD62L+CD45RO+) for CD4+ (93.70 ± 5.23%) and CD8+ (94.26 ± 4.04%). The functional assessments in 2D and 3D cell culture assays showed that TCR-T cells mounted a polyfunctional response to the cognate HCV peptide target in tumor cell lines, including killing. Collectively, we report a solid strategy for the efficient large-scale manufacturing of TCR-T cells.

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Immunotherapeutic Potential of T Memory Stem Cells

Cited by 24 publications

References 165 publications

Metabolic plasticity and regulation of T cell exhaustion

Metabolic plasticity and regulation of T cell exhaustion

Efficient derivation of chimeric-antigen receptor-modified TSCM cells

Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products

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