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Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas

Nature Neuroscience volume 15, pages 197–204 (2012)Cite this article

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Abstract

Therapeutically engineered stem cells have shown promise for glioblastoma multiforme (GBM) therapy; however, key preclinical studies are urgently needed for their clinical translation. In this study, we investigated a new approach to GBM treatment using therapeutic stem cells encapsulated in biodegradable, synthetic extracellular matrix (sECM) in mouse models of human GBM resection. Using multimodal imaging, we first showed quantitative surgical debulking of human GBM tumors in mice, which resulted in increased survival. Next, sECM encapsulation of engineered stem cells increased their retention in the tumor resection cavity, permitted tumor-selective migration and release of diagnostic and therapeutic proteins in vivo. Simulating the clinical scenario of GBM treatment, the release of tumor-selective S-TRAIL (secretable tumor necrosis factor apoptosis inducing ligand) from sECM-encapsulated stem cells in the resection cavity eradicated residual tumor cells by inducing caspase-mediated apoptosis, delayed tumor regrowth and significantly increased survival of mice. This study demonstrates the efficacy of encapsulated therapeutic stem cells in mouse models of GBM resection and may have implications for developing effective therapies for GBM.

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Figure 1: Tumor resection prolongs survival of mice bearing GBM.
Figure 2: Characterizing engineered mNSCs in biocompatible sECM in vitro and in vivo.
Figure 3: mNSCs expressing therapeutic S-TRAIL induce GBM cell death in vitro.
Figure 4: sECM-encapsulated mNSC-S-TRAIL cells transplanted into the tumor resection cavity increase survival of mice.
Figure 5: sECM-encapsulated therapeutic human MSCs have anti-tumor effects on primary invasive human GBMs in vitro and in vivo.

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Acknowledgements

We thank G. Prestwich (University of Utah) and T. Zarembinski (Biotime Inc.) for providing us with sECMs, H. Wakimoto (Massachusetts General Hospital) for providing the primary GBM lines and D. Bhere for critical reading of the manuscript. This work was supported by the Alliance for Cancer Cell and Gene Therapy (K.S.), American Cancer Society (K.S.) and James McDonald Foundation (K.S.).

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Authors and Affiliations

  1. Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Timo M Kauer, Jose-Luiz Figueiredo, Shawn Hingtgen & Khalid Shah

  2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Timo M Kauer, Jose-Luiz Figueiredo, Shawn Hingtgen & Khalid Shah

  3. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Khalid Shah

  4. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    Khalid Shah

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  1. Timo M Kauer
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Contributions

K.S. and T.M.K. designed research; T.M.K., J.-L.F., S.H. and K.S. performed research; T.M.K., S.H. and K.S. analyzed data and wrote the paper.

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Correspondence to Khalid Shah.

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Kauer, T., Figueiredo, JL., Hingtgen, S. et al. Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. Nat Neurosci 15, 197–204 (2012). https://doi.org/10.1038/nn.3019

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