Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy

Minagawa, Atsutaka; Yoshikawa, Toshiaki; Yasukawa, Masaki; Hotta, Akitsu; Kunitomo, Mihoko; Iriguchi, Shoichi; Takiguchi, Maiko; Kassai, Yoshiaki; Imai, Eri; Yasui, Yutaka; Kawai, Yohei; Zhang, Rong; Uemura, Yukari; Miyoshi, Hiroyuki; Nakanishi, Mahito; Watanabe, Akira; Hayashi, Akira; Kawana, Kei; Fujii, Tomoyuki; Nakatsura, Tetsuya; Kaneko, Shin

doi:10.1016/j.stem.2018.10.005

Cited by 114 publications

(124 citation statements)

References 40 publications

(56 reference statements)

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“…Recently, it was reported that the iPSCs transduced with exogenous TCR gene gave rise to potent CTLs. 25 This TCR-transduction method may make it easier to produce a cell source for CTLs. However, in that paper it remained unclear whether CTLs produced from TCR-transduced iPSCs are as good as those from T-iPSCs in terms of cytotoxic activity, since these two types of CTLs were not directly compared.…”

Section: Discussionmentioning

confidence: 99%

High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells

Nagano

Maeda

Ichise

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Current adoptive T cell therapies conducted in an autologous setting are costly, time-consuming, and depend on the quality of the patient's T cells, and thus it would be highly beneficial to develop an allogeneic strategy. To this aim, we have developed a method by which cytotoxic T lymphocytes (CTLs) are regenerated from induced pluripotent stem cells that are originally derived from T cells (T-iPSCs). In order to assess the feasibility of this strategy, we investigated the frequency of usable T-iPSC clones in terms of their T cell-generating capability and T cell receptor (TCR) affinity. We first established eight clones of T-iPSCs bearing different MART-1-specific TCRs from a healthy volunteer. Whereas all clones were able to give rise to mature CTLs, cell yield varied greatly, and five clones were considered to be usable. TCR affinity in the regenerated CTLs showed a large variance among the eight clones, but functional avidities measured by cytotoxic activity were almost equivalent among three selected clones representing high, medium, and low TCR affinity. In a total of 50 alloreactivity tests using five CTL clones versus ten target cells, alloreactivity was seen in only three cases. These findings collectively support the feasibility of this T-iPSC strategy.

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Section: Discussionmentioning

confidence: 99%

High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells

Nagano

Maeda

Ichise

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…This protocol describes a recent method involving stimulation of purified CD4 + CD8 + DP cells to generate CD8αβ + SP T cells with a more conventional phenotype and improved antigen-specific cytotoxicity 22 . Although the loss of antigen specificity due to secondary TCRα allelic rearrangement occurs in the DP stage after prolonged long-term culture, this can be overcome by genome editing in T-iPSCs 31 . In our experience, hiPSC-derived DP cells start to appear on day 30 -35 of culture, and these newly generated DP cells have not yet undergone secondary TCRα rearrangement.…”

Section: Discussionmentioning

confidence: 99%

Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells

Good

Vizcardo

Maeda

et al. 2019

JoVE

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The generation and expansion of functional T cells in vitro can lead to a broad range of clinical applications. One such use is for the treatment of patients with advanced cancer. Adoptive T cell transfer (ACT) of highly enriched tumor antigen-specific T cells has been shown to cause durable regression of metastatic cancer in some patients. However, during expansion, these cells may become exhausted or senescent, limiting their effector function and persistence in vivo. Induced pluripotent stem cell (iPSC) technology may overcome these obstacles by leading to in vitro generation of large numbers of less differentiated tumor antigen-specific T cells. Human iPSC (hiPSC) have the capacity to differentiate into any type of somatic cell, including lymphocytes, which retain the original T cell receptor (TCR) genomic rearrangement when a T cell is used as a starting cell. Therefore, reprogramming of human tumor antigen-specific T cells to hiPSC followed by redifferentiation to T cell lineage has the potential to produce rejuvenated tumor antigen-specific T cells. Described here is a method for generating tumor antigen-specific CD8αβ + single positive (SP) T cells from hiPSC using OP9/DLL1 co-culture system. This method is a powerful tool for in vitro T cell lineage generation and will facilitate the development of in vitro derived T cells for use in regenerative medicine and cell-based therapies.

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“…Recent studies have challenged the rejuvenation of differentiated T cells by various approaches. Clinical trials evaluating rejuvenation of T cells using iPS technology from antigen-specific T cells (T-iPS cells) are on going [51][52][53][54]. However, a significant length of time is needed to establish iPS cells from patient T cells, and the T cells generated from iPS cells must be expanded by TCR stimulation in vitro, which may still induce T cell exhaustion.…”

Section: Application Of T Scm For Cancer Immunotherapymentioning

confidence: 99%

Memory T cell, exhaustion, and tumor immunity

Ando

Ito

Srirat

et al. 2019

Immunological Medicine

133

102

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CD8 þ T cells are important in protective immunity against intracellular pathogens and tumors. In chronic infections or cancer, CD8 þ T cells are constantly exposed to antigens and inflammatory signals. Such excessive and constitutive signals lead to the deterioration of T cell function, called 'exhaustion'. Exhausted T cells are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis. These dysfunctions are associated with altered transcriptional programs and epigenetic regulations and recent studies suggested that NR4a and TOX transcription factors are deeply involved in exhaustion phenotypes. However, an increase the early memory T cells including stem cell memory T (T SCM) cells is critical for T cell persistence and efficient tumor killing especially for adoptive cancer immunotherapy such as CART cell therapy. An increasing amount of evidence supports the therapeutic potential of targeting exhausted T cells and T SCM cells. We have begun to understand the molecular mechanisms of T cell exhaustion and early memory formation, and the clinical application of converting exhausted T cells to rejuvenated early memory T cells is the goal of our study.

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Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy

Cited by 114 publications

References 40 publications

High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells

High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells

Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells

Memory T cell, exhaustion, and tumor immunity

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