Strategies for Genetically Engineering Hypoimmunogenic Universal Pluripotent Stem Cells

Zhao, Wei; Lei, Anhua; Tian, Lin; Wang, Xudong; Correia, Cristina; Weiskittel, Taylor M.; Li, Hu; Trounson, Alan; Fu, Qiang; Yao, Ke; Zhang, Jin

doi:10.1016/j.isci.2020.101162

Cited by 32 publications

(36 citation statements)

References 71 publications

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“…Context-aware design is particularly important for the therapeutic use of cell therapies. Expected challenges such as the inability to engraft and graft-versus-host disease (GVHD) can be approached by engineering signaling proteins/processes and major histocompatibility complexes in the therapeutic cells (Deuse et al, 2019;Ferreira et al, 2019;Han et al, 2019;Raffin et al, 2020;Zhao et al, 2020). With control systems in place, the expression of such elements can be made to adapt to the local environment, further improving the chance of successful engraftment for individual cells and perhaps even entire tissues.…”

Section: Controlling Therapeutic Cell Functionmentioning

confidence: 99%

Context-aware synthetic biology by controller design: Engineering the mammalian cell

2021

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Section: Controlling Therapeutic Cell Functionmentioning

confidence: 99%

Context-aware synthetic biology by controller design: Engineering the mammalian cell

2021

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“…iPSCs offer a unique opportunity to circumvent the immunological barriers to transplantation, and, as reviewed elsewhere ( 47 , 48 ), a number of strategies are being explored to reduce the potential immunogenicity of the iPSC (or ESC)-derived biological transplantation material. The three main strategies, autologous, HLA homozygous and HLA depleted, are discussed here ( Figure 2 ).…”

Section: Strategies To Circumvent Immune Rejection Against Ipsc-derivmentioning

confidence: 99%

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

et al. 2021

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Human induced pluripotent stem cells (iPSCs) can be limitlessly expanded and differentiated into almost all cell types. Moreover, they are amenable to gene manipulation and, because they are established from somatic cells, can be established from essentially any person. Based on these characteristics, iPSCs have been extensively studied as cell sources for tissue grafts, blood transfusions and cancer immunotherapies, and related clinical trials have started. From an immune-matching perspective, autologous iPSCs are perfectly compatible in principle, but also require a prolonged time for reaching the final products, have high cost, and person-to-person variation hindering their common use. Therefore, certified iPSCs with reduced immunogenicity are expected to become off-the-shelf sources, such as those made from human leukocyte antigen (HLA)-homozygous individuals or genetically modified for HLA depletion. Preclinical tests using immunodeficient mice reconstituted with a human immune system (HIS) serve as an important tool to assess the human alloresponse against iPSC-derived cells. Especially, HIS mice reconstituted with not only human T cells but also human natural killer (NK) cells are considered crucial. NK cells attack so-called “missing self” cells that do not express self HLA class I, which include HLA-homozygous cells that express only one allele type and HLA-depleted cells. However, conventional HIS mice lack enough reconstituted human NK cells for these tests. Several measures have been developed to overcome this issue including the administration of cytokines that enhance NK cell expansion, such as IL-2 and IL-15, the administration of vectors that express those cytokines, and genetic manipulation to express the cytokines or to enhance the reconstitution of human myeloid cells that express IL15R-alpha. Using such HIS mice with enhanced human NK cell reconstitution, alloresponses against HLA-homozygous and HLA-depleted cells have been studied. However, most studies used HLA-downregulated tumor cells as the target cells and tested in vitro after purifying human cells from HIS mice. In this review, we give an overview of the current state of iPSCs in cell therapies, strategies to lessen their immunogenic potential, and then expound on the development of HIS mice with reconstituted NK cells, followed by their utilization in evaluating future universal HLA-engineered iPSC-derived cells.

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“…Independently of the number of doses infused and of the intensity of lymphodepletion, reducing the immunogenicity of allogeneic CAR T cells is always desired, and one direct approach is the genetic abrogation of MHC class I molecules ( Figure 2 ). Despite being highly polymorphic molecules, all share the β2-microglobulin protein, and disrupting this subunit allows the elimination of all MHC class I molecules at the T cell surface ( 98 , 99 ). A second level of allorejection could be mediated via the presence of HLA class II molecules on CAR T cells.…”

Section: Allogeneic Car T Cellsmentioning

confidence: 99%

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

2021

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Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range of solid tumors have made CAR T cells one of the most promising fields for cancer therapies. CAR T cell therapy is currently being investigated in solid tumors including glioblastoma (GBM), a tumor for which survival has only modestly improved over the past decades. CAR T cells targeting EGFRvIII, Her2, or IL-13Rα2 have been tested in GBM, but the first clinical trials have shown modest results, potentially due to GBM heterogeneity and to the presence of an immunosuppressive microenvironment. Until now, the use of autologous T cells to manufacture CAR products has been the norm, but this approach has several disadvantages regarding production time, cost, manufacturing delay and dependence on functional fitness of patient T cells, often reduced by the disease or previous therapies. Universal “off-the-shelf,” or allogeneic, CAR T cells is an alternative that can potentially overcome these issues, and allow for multiple modifications and CAR combinations to target multiple tumor antigens and avoid tumor escape. Advances in genome editing tools, especially via CRISPR/Cas9, might allow overcoming the two main limitations of allogeneic CAR T cells product, i.e., graft-vs.-host disease and host allorejection. Here, we will discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM.

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Strategies for Genetically Engineering Hypoimmunogenic Universal Pluripotent Stem Cells

Cited by 32 publications

References 71 publications

Context-aware synthetic biology by controller design: Engineering the mammalian cell

Context-aware synthetic biology by controller design: Engineering the mammalian cell

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

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