Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells

Wang, Bo; Iriguchi, Shoichi; Waseda, Masazumi; Ueda, Naonori; Ueda, Toshihisa; Xu, Huaigeng; Minagawa, Atsutaka; Ishikawa, Akihiro; Yano, Hisashi; Ishi, Tomoko; Ito, Ryoji; Goto, Motohito; Takahashi, Riichi; Uemura, Yukari; Hotta, Akitsu; Kaneko, Shin

doi:10.1038/s41551-021-00730-z

Cited by 111 publications

(96 citation statements)

References 52 publications

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“…Similar engineering in iPSC was conducted to disrupt B2M, CIITA, and CD155 (encoding an activating ligand of NK cells) and transduce HLA-E, serving as a source of CAR-T cells. These hypoimmunogenic CAR-T cells largely escaped rejection by CD8 + T cells, CD4 + T cells, and NK cells, maintaining antitumor cytotoxicity (58).…”

Section: Efficiency Of Ucar-t Cell Therapymentioning

confidence: 99%

Advances in Universal CAR-T Cell Therapy

et al. 2021

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Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

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Section: Efficiency Of Ucar-t Cell Therapymentioning

confidence: 99%

Advances in Universal CAR-T Cell Therapy

et al. 2021

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“…However, one difficulty that may arise with this solution is the potential for homozygous C1 or C2 cells to be recognised and killed by NK cells that are heterozygous for C1/ C2 (Ichise et al 2017 ). In an alternative approach, “invisible iPSC-derived T cells” were recently generated through deletion of β 2 -microglobulin, CIITA and the NK cell–ligand poliovirus receptor CD155, accompanied by expression of the NK cell-inhibitory ligand HLA-E, thereby minimising recognition by recipient cytotoxic T cells and NK cells (Wang et al 2021 ).…”

Section: Ipsc-derived Car T Cellsmentioning

confidence: 99%

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Mazza

Maher

2021

Arch. Immunol. Ther. Exp.

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Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

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“…Besides the risk of GvHD, graft rejection by the recipient's immune cells is another concern. Several groups have generated universal or hypoimmunogenic iPSC lines by eliminating HLA class Ia (HLA -A, -B, and -C) and class II molecules to avoid immune rejection by CD8 T cells and CD4 T cells, respectively, and introducing HLA class Ib (HLA-G or HLA-E) or immune checkpoint molecules (PD-L1 or CD47) to prevent NK cellmediated lysis or phagocytosis by macrophages (115)(116)(117)(118)(119)(120)(121)(122). To date, the main challenge for translating these approaches is how to avoid NK cell-mediated lysis.…”

Section: Advances Of Ipsc-derived Car T Cells For Off-the-shelf Actmentioning

confidence: 99%

“…More recently, Wang et al took a step forward by knocking out poliovirus receptor (PVR) or CD155, a ligand for NK cell-activating receptor DNAM-1, in the HLA-E-transduced, HLA-I-and HLA-II-null iPSCs. Upon differentiation toward cytotoxic T cells, the engineered cells could reduce the activation of DNAM-1 + NK cells, consisting of both NKG2A + and NKG2Apopulations, and persisted longer than the HLA-intact iPSC-derived T cells in vitro and in vivo in the presence of allogeneic immunity (119). Therefore, engineering multiple inhibitory/activating signals could lead to a more effective escape from NK cells making the iPSC-derived T cells applicable to a larger number of patients.…”

Section: Advances Of Ipsc-derived Car T Cells For Off-the-shelf Actmentioning

confidence: 99%

Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

Netsrithong

Wattanapanitch

2021

Front. Immunol.

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Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.

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Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells

Cited by 111 publications

References 52 publications

Advances in Universal CAR-T Cell Therapy

Advances in Universal CAR-T Cell Therapy

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

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