Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies

1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, California, USA. [3] Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California, USA. [4].
Nature medicine (Impact Factor: 27.36). 08/2013; 19(8):998-1004. DOI: 10.1038/nm.3267
Source: PubMed


Human pluripotent stem cells (PSCs) are a leading candidate for cell-based therapies because of their capacity for unlimited self renewal and pluripotent differentiation. These advances have recently culminated in the first-in-human PSC clinical trials by Geron, Advanced Cell Technology and the Kobe Center for Developmental Biology for the treatment of spinal cord injury and macular degeneration. Despite their therapeutic promise, a crucial hurdle for the clinical implementation of human PSCs is their potential to form tumors in vivo. In this Perspective, we present an overview of the mechanisms underlying the tumorigenic risk of human PSC-based therapies and discuss current advances in addressing these challenges.

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Available from: Mahendra Surendra Rao, Dec 26, 2013
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    • "Their pluripotency makes iPSCs a promising tool for therapy in a wide range of diseases at present refractory to treatment (Inoue et al., 2014). Recent studies, however, reported the tumorigenic potential of contaminated undifferentiated iPSCs and the malignant transformation of differentiated iPSCs (Lee et al., 2013a; Nori et al., 2015). The tumorigenic risks of iPSCs could be reduced by several strategies, such as sorting out undifferentiated cells with antibodies targeting surface-displayed biomarkers (Tang et al., 2011), killing undifferentiated cells with cytotoxic antibodies (Choo et al., 2008), or elimination of remaining undifferentiated pluripotent cells with chemical inhibitors (Ben-David et al., 2013; Lee et al., 2013b). "
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    ABSTRACT: The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "Recently, the first in-human clinical trial using hiPSC-derived retinal pigment epithelium was conducted by RIKEN Center for Developmental Biology in Kobe to treat the wet form of age-related macular degeneration (Kamao et al., 2014). However, although the clinical and industrial application of hPSC-based cell therapy is becoming an increasingly realistic prospect, a major safety concern still exists, as residual hPSCs in differentiated cell populations could form tumors in recipients (Ben-David and Benvenisty, 2011; Goldring et al., 2011; Lee et al., 2013a). "
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    ABSTRACT: The application of stem-cell-based therapies in regenerative medicine is hindered by the tumorigenic potential of residual human pluripotent stem cells. Previously, we identified a human pluripotent stem-cell-specific lectin probe, called rBC2LCN, by comprehensive glycome analysis using high-density lectin microarrays. Here we developed a recombinant lectin-toxin fusion protein of rBC2LCN with a catalytic domain of Pseudomonas aeruginosa exotoxin A, termed rBC2LCN-PE23, which could be expressed as a soluble form from the cytoplasm of Escherichia coli and purified to homogeneity by one-step affinity chromatography. rBC2LCN-PE23 bound to human pluripotent stem cells, followed by its internalization, allowing intracellular delivery of a cargo of cytotoxic protein. The addition of rBC2LCN-PE23 to the culture medium was sufficient to completely eliminate human pluripotent stem cells. Thus, rBC2LCN-PE23 has the potential to contribute to the safety of stem-cell-based therapies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Stem Cell Reports
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    • "The propensity of PSC-derived tissues for malignant transformation is a significant clinical concern as highlighted by recent reports of cancer development following the administration of neurogenic cells (Amariglio et al., 2009; Doi et al., 2012). Continuing improvements in reprogramming procedures, the selection of genetically suitable clones, and different purging strategies will clearly help attenuate the risk (Lee et al., 2013). We report an additional strategy that is rooted in the concept of cancer's ''oncogene dependence'' (Jain et al., 2002; Soucek et al., 2008; Weinstein, 2002). "
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    ABSTRACT: The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer's increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.
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