Generation of hypoimmunogenic human pluripotent stem cells

Han, Xiao; Wang, Mengning; Duan, Songwei; Franco, Paul J.; Kenty, Jennifer Hyoje-Ryu; Hedrick, Preston; Xia, Yulei; Allen, Alana; Ferreira, Leonardo M. R.; Strominger, Jack L.; Melton, Douglas A.; Meißner, Torsten; Cowan, Chad A.

doi:10.1073/pnas.1902566116

Cited by 261 publications

(248 citation statements)

References 46 publications

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“…The ability to generate hiPSCs at an affordable cost and in a timely manner will be necessary to assure the success of future hiPSC-derived cell therapies. Moreover, it will be essential to demonstrate that hiPSC-based therapies, whether using autologous donors or through the development of universal cell lines, are safe [11; 12; 13]. Here, we provide evidences that hiPSCs are the target of NK cells in vitro and in humanized mice.…”

Section: Discussionmentioning

confidence: 90%

NK cells prevent the formation of teratomas derived from human induced pluripotent stem cells

Benabdallah

Deslauniers-Langevin

Colas

et al. 2019

Preprint

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The safe utilization of induced pluripotent stem cell-derivatives in clinic is tributary to the complete elimination of the risk of forming teratomas after transplantation. The extent by which such a risk exists in immune competent hosts is mostly unknown. Here, using humanized mice reconstituted with fetal hematopoietic stem cells and autologous thymus tissue (Hu-BLT) or following the adoptive transfer of peripheral blood mononuclear cells (PBMCs) (Hu-AT), we evaluated the capacity of immune cells to prevent or eliminate teratomas derived from human induced pluripotent stem cells (hiPSCs). Our results showed that the injection of hiPSCs failed to form teratomas in Hu-AT mice reconstituted with allogeneic or autologous PBMCs or purified NK cells alone. However, teratomas were observed in Hu-AT mice reconstituted with autologous PBMCs depleted from NK cells. In line with these results, Hu-BLT which do not have functional NK cells could not prevent the growth of autologous teratomas. Finally, we found that established teratomas were not targeted by NK cells and instead were efficiently rejected by allogeneic but not autologous T cells in Hu-AT mice. Overall, our findings suggest that autologous hiPSC-derived therapies are unlikely to form teratomas in the presence of NK cells. Words: 194

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Section: Discussionmentioning

confidence: 90%

NK cells prevent the formation of teratomas derived from human induced pluripotent stem cells

Benabdallah

Deslauniers-Langevin

Colas

et al. 2019

Preprint

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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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“…We show here that the forced expression of eight immunomodulatory factors in cells is sufficient to escape immune rejection in allogeneic hosts. Other attempts to engineer allotolerated cells have focused on removing MHC genes and/or the introduction of just one or a few factors [2][3][4]32 . The emphasis on MHC genes is clearly justified since they are the primary source of allogenic antigens during transplantation and loss of these molecules is often coincident with immune evasion in nature 33 .…”

Section: Discussionmentioning

confidence: 99%

“…A recent report showed that replacement of HLA class I in human PSCs with the inhibitory HLA-E prevented NK and CD8 T-cell responses in vitro as well clearance after engraftment into humanized mouse models 2 . Others have combined deletion of MHC class I and II with the forced expression of one or more immunosuppressive transgenes 3,4 . While promising, MHC-modified or null cells still express minor antigens and other gene polymorphisms that can become targets of rejection and humoral immunity over time [5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompetent hosts

Harding

Vintersten-Nagy

Shutova

et al. 2019

Preprint

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A vast number of diseases could be treated with therapeutic cells derived from pluripotent stem cells (PSCs). However, cell products that come from non-autologous sources can be immune rejected by the recipient's immune system. Here, we show that forced expression of eight immunomodulatory transgenes, including Ccl21, Pdl1, Fasl, Serpinb9, H2-M3, Cd47, Cd200, and Mfge8, allows mouse embryonic stem cells (mESCs) and their derivatives to escape immune rejection in fully immunocompetent, allogeneic recipients. Despite no genetic alterations to major histocompatibility complex (MHC) genes, immune-modified C57BL/6 mESCs could generate long-term, allogeneic tissues in inbred FVB/N, C3H, and BALB/c, as well as outbred CD-1 recipients. Due to the tandem incorporation of our safe-cell suicide system, which allows tight and drug-inducible control over proliferation in vivo, these allotolerated cells can generate safe and dormant ectopic tissues in the host. We show that these ectopic tissues maintain high expression of all eight immunomodulatory transgenes and are immune-privileged sites that can host and protect unmodified mouse and human cells from rejection in allogeneic and xenogeneic settings, respectively. If translated to human clinical settings, we envision the development of a single pluripotent cell line that can be used to generate allo-tolerated, off-the-shelf cell products to serve all humankind, as well as immuneprivileged ectopic tissues to host and immune-protect any kind of therapeutic cell product.

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Generation of hypoimmunogenic human pluripotent stem cells

Cited by 261 publications

References 46 publications

NK cells prevent the formation of teratomas derived from human induced pluripotent stem cells

NK cells prevent the formation of teratomas derived from human induced pluripotent stem cells

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

Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompetent hosts

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