A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

Iriguchi, Shoichi; Yasui, Yutaka; Kawai, Yohei; Arima, Suguru; Kunitomo, Mihoko; Sato, Takayuki; Ueda, Toshihisa; Minagawa, Atsutaka; Mishima, Yumiko; Yanagawa, Nariaki; Baba, Yuji; Miyake, Yasuyuki; Nakayama, Keizo; Takiguchi, Maiko; Shinohara, Tetsuji; Nakatsura, Tetsuya; Yasukawa, Masaki; Kassai, Yoshiaki; Hayashi, Akira; Kaneko, Shin

doi:10.1038/s41467-020-20658-3

Cited by 128 publications

(147 citation statements)

References 47 publications

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“…The limited progression to mature SP stages is not surprising as the system lacks stromal-elements that would provide positively-selecting ligands. This could be overcome through stimulation of purified iPSC-derived CD4 + CD8 + DP cells with anti-TCR/CD3 antibodies 32 – 34 . Nonetheless, the differentiation of TCR-transduced iPSCs or re-differentiation of iPSCs from T cells enhances the efficiency of generating αβTCR-expressing T cells 32 – 34 , which was also the case in our iPSC-DL4µbeads cultures.…”

Section: Discussionmentioning

confidence: 99%

DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

et al. 2021

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T cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-μbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αβ T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-μbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.

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Section: Discussionmentioning

confidence: 99%

DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

et al. 2021

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“…The generation of immune cells from induced pluripotent stem cells (iPSCs) offer an alternative platform to produce "off-the-shelf" and synthetic allogeneic T cells [132]. Proof-ofprinciple studies support the feasibility of this approach [133,134]. iPS-derived NK cells have already entered the clinic (NCT03841110) and iPS-derived T cells will be investigated shortly in subjects with relapsed/refractory B-cell lymphoma (NCT04629729).…”

Section: T-ipsmentioning

confidence: 99%

CAR T cells: Building on the CD19 paradigm

et al. 2021

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Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B-cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence-associated pathologies.

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“…However, the maturation into CD4+ T-cells is even more challenging and requires ATO-based T-cell differentiation supported by FLT3L, SCF, and IL-7 ( 161 ). In an effort to move T-cell reprogramming further towards clinical applications, Iriguchi et al developed a clinically applicable T-cell differentiation technique based on SDF1α and p38 inhibitor, allowing differentiation without feeder layers ( 162 ). For the specification of T-cells, the somatic origin of iPSC significantly impacts differentiation.…”

Section: Immune Cell Programming and Reprogrammingmentioning

confidence: 99%

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

et al. 2021

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Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients’ immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for in vivo reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of in vitro cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells in vivo. These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells in situ, widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities in vivo, providing new and exciting tools for the fast-paced field of cancer immunotherapy.

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A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

Cited by 128 publications

References 47 publications

DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

CAR T cells: Building on the CD19 paradigm

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

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