Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility

Xu, Huaigeng; Wang, Bo; Ono, Masanori; Kagita, Akihiro; Fujii, Kaho; Sasakawa, Nobuyuki; Ueda, Toshihisa; Gee, Peter; Nishikawa, Misato; Nomura, Masaki; Kitaoka, Fumiyo; Takahashi, Tomoko; Okita, Keisuke; Yoshida, Yoshinori; Kaneko, Shin; Hotta, Akitsu

doi:10.1016/j.stem.2019.02.005

Cited by 371 publications

(303 citation statements)

References 39 publications

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“…Second, increasingly complicated genome engineering approaches can be applied to iPSCs, followed by single clone expansion and thorough characterization to obtain a clonal and genetically homogenous population with minimal off-target risk. Third, the seed iPSC clone can be expanded in large scale, and when combined with the recently reported techniques in making immune-tolerant universal iPSCs [25][26][27] , CAR-iMac can be developed into an off-the-shelf product with unlimited sources. The last two points are particularly useful when the effector cells from primary cell sources are difficult to engineer and to expand which is the case for PBMC-derived macrophage cells.…”

Section: Discussionmentioning

confidence: 99%

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Zhang

Tian

Dai

et al. 2020

Preprint

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One sentence summary:We developed CAR-expressing iPSC-induced macrophage cells that have antigen-dependent phagocytosis and pro-inflammatory functions and anti-cancer cell activity for both liquid and solid tumor cells. Abstract:The Chimera antigen receptor (CAR)-T cell therapy has gained great success in the clinic. However, there are still major challenges for its wider applications in a variety of cancer 2 types including lack of effectiveness due to the highly complex tumor microenvironment, and the forbiddingly high cost due to personalized manufacturing procedures. In order to overcome these hurdles, numerous efforts have been spent focusing on optimizing Chimera Antigen Receptors, engineering and improving T cell capacity, exploiting features of subsets of T cell or NK cells, or making off-the-shelf universal T cells. Here, we developed induced pluripotent stem cells (iPSCs)-derived, CAR-expressing macrophage cells (CAR-iMac). These cells showed antigen-dependent macrophage functions such as expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, and phagocytosis of tumor cells, as well as some in vivo anti-cancer cell activity for both liquid and solid tumors. This technology platform for the first time provides an unlimited source of iPSC-derived engineered CARmacrophage cells which could be utilized to eliminate cancer cells or modulate the tumor microenvironment in liquid and solid tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Zhang

Tian

Dai

et al. 2020

Preprint

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“…T lymphocytes attack malignant and virus-infected cells with the help of antigen-specific TCR [47]. More recently, iPSCs with enhanced immune-evading capacity have been established [49,50]. To generate abundant 'young' T cells, Nishimura et al have reported the derivation of iPSCs from CD8 + T cells collected from the peripheral blood of an HIV patient [17].…”

Section: Therapeutic Applications Of Blood Reprogrammingmentioning

confidence: 99%

“…Antigenspecific T cells have excellent potential to alleviate the condition when injected to patients with cancer or virus infection. Engineered iPSCs are shown to circumvent both immune T and NK cells when knocked out of human leucocyte antigens (HLAs) A and B via CRISPR, while retaining one allele of HLA-C [50]. Upon redifferentiation, iPSC-derived T cells not only exhibit the same antigenspecific killing activity, but also display a more 'rejuvenated' phenotype with a significantly higher proliferative capacity compared with the original T cells.…”

Section: Therapeutic Applications Of Blood Reprogrammingmentioning

confidence: 99%

“…Since genetically modified B cells have been developed to generate anti-HIV-1 neutralizing antibodies (bNAbs) [48], clinically potent monoclonal B cells derived from iPSCs are considered to be a viable source of such antibodies. More recently, iPSCs with enhanced immune-evading capacity have been established [49,50]. Engineered iPSCs are shown to circumvent both immune T and NK cells when knocked out of human leucocyte antigens (HLAs) A and B via CRISPR, while retaining one allele of HLA-C [50].…”

Section: Therapeutic Applications Of Blood Reprogrammingmentioning

confidence: 99%

“…More recently, iPSCs with enhanced immune-evading capacity have been established [49,50]. Engineered iPSCs are shown to circumvent both immune T and NK cells when knocked out of human leucocyte antigens (HLAs) A and B via CRISPR, while retaining one allele of HLA-C [50]. These techniques will facilitate the development of allogeneic iPSC therapy, as an iPSC line can potentially be used for multiple patients without the risk of immune rejection.…”

Section: Therapeutic Applications Of Blood Reprogrammingmentioning

confidence: 99%

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Re‐entering the pluripotent state from blood lineage: promises and pitfalls of blood reprogramming

Chen

Yao

et al. 2019

FEBS Letters

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Edited by Catherine RobinBlood reprogramming, in which induced pluripotent stem cells (iPSCs) are derived from haematopoietic lineages, has rapidly advanced over the past decade. Since the first report using human blood, haematopoietic cell types from various sources, such as the peripheral bone marrow and cord blood, have been successfully reprogrammed. The volume of blood required has also decreased, from around tens of millilitres to a single finger-prick drop. Besides, while early studies were limited to reprogramming methods relying on viral integration, nonintegrating reprogramming systems for blood lineages have been subsequently established. Together, these improvements have made feasible the future clinical applications of blood-derived iPSCs. Here, we review the progress in blood reprogramming from various perspectives, including the starting materials and subsequent reprogramming strategies. We also discuss the downstream applications of blood-derived iPSCs, highlighting their clinical value in terms of disease modelling and therapeutic development.

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HLA‐E^high/HLA‐G^high/HLA‐II^low Human iPSC‐Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration

Fang,

Wang,

Liao

et al. 2023

Adv Healthcare Materials

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Although human induced pluripotent stem cells (hiPSCs)‐derived cardiomyocytes (hiPSC‐CMs) can remuscularize infarcted hearts and restore post‐infarct cardiac function, post‐transplant rejection resulting from human leukocyte antigen (HLA) mismatching is an enormous obstacle of cell therapy. Therefore, it is crucial to identify hypoimmunogenic hiPSCs for allogeneic cell therapy. We conducted this study to demonstrate the immune privilege of HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐derived cardiomyocytes (hiPSC‐CMs) in vitro. Then we did ischemia‐reperfusion surgery to create transmural myocardial infarction in rats. At post‐infarct 4 days, we injected hPSC‐CMs (1.0×107 cells/kg), including human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs), hiPSC‐CMs and HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs, into the infarcted myocardium. Compared with hESC‐CMs and hiPSC‐CMs, under the treatment of very low dose cyclosporine A (CsA), only HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CM survived in vivo, remuscularized the infarcted myocardium with infarct size reduction and improved post‐infarct cardiac function. HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs evaded attack by natural killer (NK) cells and cytotoxic T cells because these hiPSC‐CMs activated the SHP‐1 signaling pathway of NK cells and cytotoxic T cells which downregulated STAT‐1 and NF‐κB expression. Herein, we demonstrated that using clinically relevant CsA dose, HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs repaired the infarcted myocardium and restored the post‐infarct heart function. HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSCs are less immunogenic and may serve as platforms for regeneration medicine.This article is protected by copyright. All rights reserved

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Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility

Cited by 371 publications

References 39 publications

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Re‐entering the pluripotent state from blood lineage: promises and pitfalls of blood reprogramming

HLA‐E^high/HLA‐G^high/HLA‐II^low Human iPSC‐Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration

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Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility

Cited by 371 publications

References 39 publications

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Re‐entering the pluripotent state from blood lineage: promises and pitfalls of blood reprogramming

HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow Human iPSC‐Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration

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Product

Resources

About

HLA‐E^high/HLA‐G^high/HLA‐II^low Human iPSC‐Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration