Open access peer-reviewed chapter

Stem Cell Research for the Treatment of Malignant Glioma

Written By

Ryota Tamura and Masahiro Toda

Submitted: 16 October 2017 Reviewed: 15 November 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.72504

From the Edited Volume

Brain Tumors - An Update

Edited by Amit Agrawal, Luis Rafael Moscote-Salazar

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Glioblastoma is the most aggressive brain tumor. Gene therapies, such as cytokine-based, suicide gene, and oncolytic virus therapies, are different types of treatments from chemotherapy such as using temozolomide as a standard treatment. However, overall survival was not prolonged in some clinical trials because of the low efficiency of gene transduction and viral infection. Neural stem cells (NSCs) have tumor trophic migratory capacity and can be cellular delivery vehicles of cytokines, suicide genes, and oncolytic virus. NSCs can be differentiated from embryonic stem cells. In addition, mesenchymal stem cells can be another cellular delivery vehicle. Recently, induced pluripotent stem cells (iPSCs) have been established. iPSCs are multipotent; hence, they can efficiently differentiate to NSCs and can possibly overcome ethical and practical issues in clinical application. In this study, current topics about stem cell therapy for malignant glioma are reviewed.


  • malignant glioma
  • gene therapy
  • stem cell

1. Introduction

Malignant glioma is the most aggressive brain tumor that accounts for approximately 30% of all brain tumors [64]. It is incurable by a conventional standard therapy (maximal tumor resection, adjuvant chemotherapy, and irradiation) because brain tumor stem cells have infiltrative growth and resistance to irradiation and tumoricidal agents [63].

Gene therapies, such as cytokine-based, suicide gene, and oncolytic virus therapies, are different types of treatments from chemotherapy, such as using temozolomide, an alkylating agent, as a standard treatment for glioblastoma [15, 25, 56]. Some clinical trials have been previously conducted; however, prolonged overall survival was not attained. This result was caused by the low efficiency of gene transduction and viral infection [56].

Recent studies demonstrated that neural stem cells (NSCs) and mesenchymal stem cells (MSCs) have tumor trophic migratory capacity [45, 62]. NSCs and MSCs would be possible cellular delivery vehicles of cytokines, suicide genes, or oncolytic virus to tackle gliomas [45, 62]. NSCs can be differentiated from certain types of stem cells. Embryonic stem cells (ESCs) are established from the inner cell mass in human embryos; however, ESCs have ethical issues [73]. MSCs can be easily harvested from the adult bone marrow and the fatty tissue. However, further investigation is needed for the affinity of MSCs to the human brain [31]. Induced pluripotent stem cells (iPSCs) were established from human adult fibroblasts in 2007 [65, 67]. iPSCs have multipotency; hence, they can efficiently differentiate to NSCs. iPSCs can possibly overcome ethical and practical issues in clinical application [6, 66].

In this study, current topics about stem cell therapy for malignant glioma are reviewed (Figure 1).

Figure 1.

Viral vectors are tools commonly used to deliver genetic material into tumor cells. However, the efficiency of gene transduction by the viral vectors is not high enough to cover the invaded area of malignant glioma. Replication-competent virus is used for oncolytic virus therapy. Genetically modified oncolytic virus can selectively replicate in tumor cells. Viral particles are released and spread to surrounding tumor cells. Some stem cells have tumor trophic migratory capacity, which can be possible cellular delivery vehicles of cytokines, suicide genes, or oncolytic virus to tackle malignant gliomas. Stem cells have the possibility to cover the large invaded area of malignant glioma.


2. Gene therapy using viral vector

The characteristics of gene therapies are summarized in Table 1.

Gene therapyCharacteristicsTypes
Cytokine based therapyCytokine based therapy can increase the proliferation of cytotoxic T cells and natural killer cells, enhancing anticancer immune response.IL-2, IL-4, IL-12, IL-18, GM-CSF, IFN-γ, B7-1, and TGF-β antisense
Oncolytic virus therapyGenetically modified oncolytic viral vectors can selectively replicate in tumor cells. Viral particles are released and spread to surrounding tumor cells.First generation: HSV1716: γ34.5 gene deleted HSV-1
Second generation: G207: a doubly mutated HSV-1, which has deletion of both γ34.5 loci and insertional inactivation of UL39
Third generation: G47 delta: a new type of oncolytic HSV-1 derived from G207, with an additional deletion of ICP47 and the promoter region of US11
Suicide gene therapySuicide genes can change a nontoxic prodrug into a toxic substance that triggers apoptosis of tumor cells.Suicide gene/prodrug
• HSVtk/ganciclovirl
• CD/5-flucytosine

Table 1.

Characteristics of gene therapies.

CD: cytosine deaminase, GM-CSF: granulocyte–macrophage colony-stimulating factor, HSV: herpes simples virus, IFN-γ: interleukin interferon-gamma, IL: interleukin, TGF-β:transforming growth factor-beta, tk: thymidine kinase.

2.1. Cytokine-based therapy

Viral vectors such as retrovirus and adenovirus with genes encoding immunostimulatory cytokines have been used to treat malignant glioma. This therapy can increase the proliferation of cytotoxic T cells and natural killer cells, enhancing anticancer immune response. Cytokines delivered by viral vectors such as interleukin (IL)-2, IL-4, IL-12, and IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), costimulating factor such as B7–1, and enhancer of immunogenicity such as transforming growth factor-β antisense have been previously investigated. These studies demonstrated the local augmentation and ability of the immune response against glioma cells [53, 71, 74].

Recently, tumor suppressor genes are also used for gene therapy to treat malignant glioma. p53, which is known as a common mutagenic target in the development of malignant glioma, was evaluated using a replication-deficient adenoviral vector [32]. Phosphatase and tensin homolog (PTEN) negatively regulates PI3K. PTEN gene alterations are also associated with poor prognosis of malignant glioma. PTEN expression induced by adenoviral vector also showed an antitumor response in some experiments [1]. A clinical trial using an adenoviral vector with INF-β has also been conducted. However, the efficacy of that clinical trial in patients is limited. Therefore, improvement of the vector is certainly necessary to deliver the genes [14]. On the contrary, some studies suggested the advantages of the combination of cytokine-based and standard chemotherapies. In the future, combinatorial gene therapy might be effective in the treatment of malignant glioma [11, 33, 44, 76].

2.2. Oncolytic virus therapy

Replication-competent viral vectors have been previously used for oncolytic virus therapy. The transduction efficiency of replication-competent viral vectors is higher than that of replication-deficient viral vectors [2]. Genetically modified oncolytic viral vectors can selectively replicate in tumor cells. Viral particles are released and spread to surrounding tumor cells. Oncolytic viral vectors cannot replicate in normal cells. Herpes simplex virus (HSV)-1 is the most famous oncolytic virus that has lower immunogenicity and stronger tumoricidal effects than adenovirus [22, 70].

HSV1716 is γ34.5 gene deleted HSV-1, constructed from wild-type strain. The γ34.5 gene of HSV-1 encodes ICP34.5. ICP34.5 gene counteracts the double-stranded RNA-dependent protein kinase (PKR)-mediated block to virus replication in post-mitotic cells. HSV1716 effectively kills tumor cells because tumor cells have weaker defenses mediated by PKR pathway. The safety and toxicity of HSV1716 in patients have been demonstrated in a phase I clinical trial for recurrent malignant glioma. Moreover, major neurological manifestation was not noted [55]. However, HSV1716 has the risk of being converted to the wild-type strain HSV-1 because HSV1716 has only single gene deletion [18, 52].

G207 is a doubly mutated HSV-1, which has deletion of both γ34.5 loci and insertional inactivation of UL39. Ribonucleotide reductase (RR) encoded by UL39 is crucial for virus replication by catalyzing ribonucleotide formation. The lack of viral RR expression in G207 specifically targets tumor cells because tumor cells have high RR activity. In addition, G207 did not have the risk of being converted to the wild-type strain HSV-1. G207 was safe when it was inoculated into patients with recurrent malignant glioma in phase I or Ib clinical trials. Treatment-related toxicity or serious adverse events and evidence of HSV-1 encephalitis were not shown [39, 40, 42].

G47 delta is a new type of oncolytic HSV-1. G47 delta has an additional deletion of the gene encoding ICP47. G47 delta has the ability to enhance major histocompatibility complex class I antigen and immune response. In addition, this deletion causes promoter shift for the unique short 11 gene, which blocks the effect of IFNs and increases viral replication in tumor cells. A phase I/IIa clinical trial using G47 delta, which enhances specificity, and safety was conducted for recurrent or progressive glioblastoma in 2009 [72]. A phase II clinical trial using G47 delta was initiated from 2015 in a physician-led clinical trial.

OncoVEXGM−CSF is a first-in-class oncolytic vaccine approved by the FDA in 2015. It helps stimulate host immune response. ICP34.5 and ICP47 were deleted from HSV-1, and the gene encoding GM-CSF was inserted. A phase I clinical trial using OncoVEXGM−CSF was conducted for patients with breast, head and neck, and gastrointestinal cancers and malignant melanoma who had unsuccessful prior therapy. In the clinical trial, the virus had a good safety profile [24]. A phase II clinical trial for patients with unresectable metastatic melanoma showed 26% response rate [60]. Moreover, a phase III clinical trial showed significant prolonged overall survival for unresectable metastatic melanoma [27, 54].

Reovirus (Reolysin), which is a naturally occurring nonpathogenic, double-stranded RNA virus, has oncolytic activity and was also approved by the FDA. It was evaluated in phase I–III clinical trials in squamous cell carcinoma of the lungs and non-small-cell lung, pancreatic, and ovarian cancers. Its favorable toxicity profile, deficiency of viral shedding, and therapeutic effect have been shown in those clinical trials. A phase III trial of Reolysin combined with paclitaxel and carboplatin for treatment of head and neck squamous cell carcinoma was completed in 2014 [43].

The 55-kda protein from the E1B region of an adenovirus binds to and inactivates the p53 gene. ONYX-015 is an adenovirus modified to selectively replicate and kill cells that harbor p53 mutations [20]. A phase I clinical trial was conducted for patients with recurrent malignant glioma. ONYX-015 showed promising safety profile; however, there was no significant therapeutic benefit [10].

Oncolytic virus therapy has been centered on various types of cancers and is expected to be applied for brain tumors. However, diffuse infiltration capacity of oncolytic virus to cover a large area invaded by malignant glioma might be one of the issues to solve.

2.3. Suicide gene therapy

Suicide genes can change a nontoxic prodrug into a toxic substance that triggers apoptosis of tumor cells [8, 69]. Herpes simplex virus thymidine kinase (HSVtk) + ganciclovir and cytosine deaminase (CD) + 5-flucytosine is the most famous combination. This therapy has a bystander killing effect, which results in the killing of a larger portion of cells than is transduced with the suicide gene [57]. In the 1990s, some clinical trials were conducted using viral vectors and fibroblasts that produce retrovirus for gene transduction. However, this therapy did not prolong the overall survival of patients with glioblastoma. This was considered to be caused by the vector’s low efficiency of gene transduction [9]. Toca 511, a retroviral replicating vector that delivers yeast CD, showed good results under the Toca FC administration in experimental brain tumor models, leading to a clinical trial [51].

2.4. Some types of stem cells

2.4.1. ESC

ESCs are derived from inner cell mass that can differentiate to triploblastic tissues. It has high telomerase activity that can persistently divide [30, 59]. Because the generation of ESCs involves the destruction of the preimplantation stage embryo, their use was controversial. In addition, ESCs can possibly lead to teratoma formation after transplantation. ESCs are also affected by immune rejection accompanied with ethical concerns because a fertile ovum is used. The first clinical trial that used ESCs was conducted in patients with severe subacute spinal injury in 2009. In that study, oligodendrocyte progenitor cells derived from ESCs were transplanted. Other clinical trials using ESCs have been previously conducted for some diseases such as age-related macular degeneration and Stargardt disease. However, it has not been applied for brain tumor [59, 80].

2.4.2. MSC

MSCs can be harvested from fetal Wharton’s jelly adult bone marrow, synovialis, fatty tissue, placenta, heart and liver. MSCs can be established by patients themselves. MSCs are not affected by host immune rejection [75]. Therefore MSCs tend to be easily linked to clinical applications. For example, endocapillary cells, myocardium, skeleton muscle, liver cell, neuron, glial cell, insulin-producing cell and epithelial cell can be differentiated from MSCs. MSCs have been previously used for clinical trials such as head injury and cerebral infarction [23, 30].

2.4.3. iPSC

iPSCs can be established directly from adult cells. Four specific genes (Oct3/4, c-myc, Sox2, and Klf4) encoding transcription factors could convert adult cells into iPSCs. iPSCs hold great promise in the field of regenerative medicine. iPSCs can also overcome some problems such as ethical concerns and immune rejection. Recently, iPSCs can be established without c-myc and can prevent teratoma formation [46, 49]. An episomal vector is used for the transduction to prevent chromosomal insertion that cannot be accomplished by viral and plasmid vectors [50, 77]. In addition, iPSCs can be cultured under the feeder-free condition, and laminin-511 supports the stable culture of iPSCs [19]. The efficiency to culture iPSCs has been rapidly improved.

The first clinical trial for macular degeneration using autologous-induced stem cell-derived retinal cells has been completed in Japan in 2015. The feasibility of using iPSCs has been shown [38]. A clinical trial for Parkinson’s disease is expected to use iPSCs in the near future [12, 13, 16, 26, 48].

All types of stem cells have two important effects. First is the trophic effect, that is, supplying various nutrients and tissue-protective cytokines, and the second is the repairing effect, that is, identifying the damaged area and differentiating to an organized tissue after homing [23, 30].

2.5. Gene therapy using stem cells as delivery vehicle

2.5.1. Cytokine-based therapy

IL-4-producing NSCs showed powerful antitumor effects compared with that of the virus-mediated delivery of IL-4 [7]. In addition, NSCs and MSCs that produce IL-2, IL-7, IL-12, and IL-23 have been evaluated for brain tumor [15, 17, 47, 61, 78, 79]. TNF-related apoptosis-inducing ligand (TRAIL) triggers caspase-8-dependent apoptosis. The tumor-specific therapeutic effects of TRAIL-producing NSCs, MSCs, and ESCs-derived astrocytes have been shown in experimental gliomas [29, 58].

2.5.2. Oncolytic virus therapy

Some studies showed the advantages of stem cells (NSCs and MSCs) to deliver replicating HSV and adenovirus because stem cells suppress the host immune response of the virus. In addition, stem cell therapy has become a promising approach because it can deliver viruses at further distance within the invaded malignant glioma [3, 5, 21, 68]. Actually, MSCs with replicating adenovirus showed that MSCs can suppress the immune response against the virus, which makes it possible to prolong viral activity and survival [4]. Some similar researches using NSCs with conditionally replicating HSV and adenovirus in preclinical studies were conducted [21].

2.5.3. Suicide gene therapy

Some reports showed that suicide gene therapy with HSVtk or CD using NSCs as cellular delivery vehicle could significantly prolong survival in animal models of brain tumor [28, 34, 37]. MSCs with HSVtk or CD were also used for the treatment of malignant glioma. Both NSCs and MSCs could migrate even to the contralateral tumor [35, 41]. Mouse iPSC-derived NSCs with HSVtk have been previously reported and showed equivalent results as described above. However, the study using human iPSC-derived NSCs has not been reported, yet [36]. One pilot trial using NSCs with CD has been recently completed, but results are not yet available.


3. Future directions

The treatment concept of gene therapy was appropriate for malignant glioma; however, viral vectors are not enough to cover the large invasion area. The migration ability of stem cells has been expected. Some types of stem cells can be established recently. However, a comparative analysis on which type of stem cell has the strongest migration ability and the tumoricidal effect is needed. In brain tumor, NSCs may be considered as the most effective cellular vehicle because of their affinity to the brain. iPSCs are attractive tools because NSCs could be efficiently differentiated from iPSCs. Gene therapy using stem cells as cellular delivery vehicles is expected to be further developed in the future.


Conflict of interest

The authors have no personal financial or institutional interest in this article.


  1. 1. Abe T, Terada K, Wakimoto H, Inoue R, Tyminski E, Bookstein R, Basilion JP, Chiocca EAPTEN. Decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli. Cancer Research. 2003;63:2300-2305
  2. 2. Aghi M, Martuza RL. Oncolytic viral therapies—The clinical experience. Oncogene. 2005;24:7802-7816
  3. 3. Ahmed AU, Alexiades NG, Lesniak MS. The use of neural stem cells in cancer gene therapy: Predicting the path to the clinic. Current Opinion in Molecular Therapeutics. 2010;12:546-552
  4. 4. Ahmed AU, Rolle CE, Tyler MA, Han Y, Sengupta S, Wainwright DA, Balyasnikova IV, Ulasov IV, Lesniak MS. Bone marrow mesenchymal stem cells loaded with an oncolytic adenovirus suppress the anti-adenoviral immune response in the cotton rat model. Molecular Therapy. 2010;18:1846-1856
  5. 5. Ahmed AU, Thaci B, Alexiades NG, Han Y, Qian S, Liu F, Balyasnikova IV, Ulasov IY, Aboody KS, Lesniak MS. Neural stem cell-based cell carriers enhance therapeutic efficacy of an oncolytic adenovirus in an orthotopic mouse model of human glioblastoma. Molecular Therapy. 2011;19:1714-1726
  6. 6. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, Sugiura M, Ideno H, Shimada A, Nifuji A, Abe M. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature. 2013;494:100-104
  7. 7. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G. Gene therapy of experimental brain tumors using neural progenitor cells. Nature Medicine. 2000;6:447-450
  8. 8. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science. 1997;276:1719-1724
  9. 9. Chen CH. Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir mediated cytotoxicity and the bystander effect. Human Gene Therapy. 1995;6:1467-1476
  10. 10. Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, Kracher J, Grossman SA, Fisher JD, Carson K, Rosenblum M, Mikkelsen T, Olson J, Markert J, Rosenfeld S, Nabors LB, Brem S, Phuphanich S, Freeman S, Kaplan R, Zwiebel JA. Phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Molecular Therapy. 2004;10:958-966
  11. 11. Chiocca EA, Smith KM, McKinney B, Palmer CA, Rosenfeld S, Lillehei K, Hamilton A, DeMasters BK, Judy K, Kirn DA. Phase I trial of Ad.hIFN-beta gene therapy for glioma. Molecular Therapy. 2008;16:618-626
  12. 12. De Lazaro, Yilmazer A, Kostarelos K. Induced pluripotent stem (iPS) cells: A new source for cell-based therapeutics? Journal of Controlled Release. 2014;185:37-44
  13. 13. Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, Sekiguchi K, Nakagawa M, Parmar M, Takahashi J. Isolation of human induced pluripotent stem cell-derived dopamineragic progenitors by cell sorting for successful transplantation. Stem Cell Reports. 2014;2:337-350
  14. 14. Eck SL, Alavi JB, Judy K, Phillips P, Alavi A, Hackney D, Cross P, Hughes J, Gao G, Wilson JM, Propert K. Treatment of recurrent or progressive malignant glioma with a recombinant adenovirus expressing human interferon-beta (H5.010CMVhIFN-beta): A phase I trial. Human Gene Therapy. 2001;12:97-113
  15. 15. Ehtesham M, Kabos P, Gutierrez M, Chung N, Griffith T, Black K, Yu J. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Research. 2002;62:7170-7174
  16. 16. Gotoh S, Ito I, Nagasaki T, Yamamoto T, Konishi S, Korogi Y, Matsumoto H, Muro S, Hirai T, Funato M, Mae S, Toyoda T, Sato-Otsubo A, Ogawa S, Osafune K, Mishima M. Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. Stem Cell Reports. 2014;3:1-10
  17. 17. Gunnarsson S, Bexell D, Svensson A, Siesjö P, Darabi A, Bengzon J. Intratumoral IL-7 delivery by mesenchymal stromal cells potentiates IFNgamma-transduced tumor cell immunotherapy of experimental glioma. Journal of Neuroimmunology. 2010;218:140-144
  18. 18. Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, Hadley D, Patterson J, Brown SM, Rampling R. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: Safety data and long-term survival. Gene Therapy. 2004;11:1648-1658
  19. 19. Hayashi Y, Chan T, Warashina M, Fukuda M, Ariizumi T, Okabayashi K, Takayama N, Otsu M, Eto K, Furue MK, Michiue T, Ohnuma K, Nakauchi H, Asashima M. Reduction of N-glycolylneuraminic acid in human induced pluripotent stem cells generated or cultured under feeder-and serum-free defined conditions. PLoS One. 2010;5:e14099
  20. 20. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Medicine. 1997;3:639-645
  21. 21. Herrlinger U, Woiciechowski C, Sena-Esteves M, Aboody KS, Jacobs AH, Rainov NG, Snyder EY, Breakefield XO. Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Molecular Therapy. 2000;1:347-357
  22. 22. Hoffmann D, Wildner O. Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment. Cancer Gene Therapy. 2007;14:627-639
  23. 23. Horita Y, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Intravenous administration of glial cell line derived neutrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Journal of Neuroscience Research. 2006;84:1495-1504
  24. 24. Hu JC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, Harrington KJ, James ND, Love CA, McNeish I, Medley LC, Michael A, Nutting CM, Pandha HS, Shorrock CA, Simpson J, Steiner J, Steven NM, Wright D, Coombes RC. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clinical Cancer Research. 2006;12:6737-6747
  25. 25. Ikeda K, Ichikawa T, Wakimoto H, Silver JS, Deisboeck TS, Finkelstein D, Harsh GR 4th, Louis DN, Bartus RT, Hochberg FH, Chiocca EA. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nature Medicine. 1999;5:881-887
  26. 26. Kamao H, Mandai M, Okamoto S, Sakai N, Suga A, Sugita S, Kiryu J, Takahashi M. Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Reports. 2014;2:205-218
  27. 27. Kaufman HL, Bines SDOPTIM. Trial: A phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncology. 2010;6:941-949
  28. 28. Kim JH, Kim JY, Kim SU, Cho KG. Therapeutic effect of genetically modified human neural stem cells encoding cytosine deaminase on experimental glioma. Biochemical and Biophysical Research Communications. 2012;417:534-540
  29. 29. Kim SM, Lim JY, Park SI, Jeong CH, JH O, Jeong M, Oh W, Park SH, Sung YC, Jeun SS. Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer Research. 2008;68:9614-9623
  30. 30. Kumagai G, Okada Y, Yamane J, Nagoshi N, Kitamura K, Mukaino M, Tsuji O, Fujiyoshi K, Katoh H, Okada S, Shibata S, Matsuzaki Y, Toh S, Toyama Y, Nakamura M, Okano H. Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury. PLoS One. 2009;4:e7706
  31. 31. Kuroda Y, Kitada M, Wakao S, Dezawa M. Bone marrow mesenchymal cells: How do they contribute to tissue repair and are they really stem cells? Archivum Immunologiae et Therapiae Experimentalis. 2011;59:369-378
  32. 32. Kwiatkowska A, Nandhu MS, Behera P, Chiocca EA, Viapiano MS. Strategies in gene therapy for glioblastoma. Cancers (Basel). 2013;5:1271-1305
  33. 33. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK, Phase I. Trial of adenovirus-mediated p53 gene therapy for recurrent glioma: Biological and clinical results. Journal of Clinical Oncology. 2003;21:2508-2518
  34. 34. Leten C, Trekker J, Struys T, Roobrouck VD, Dresselaers T, Vande Velde G, Lambrichts I, Verfaillie CM, Himmelreich U. Monitoring the bystander killing effect of human multipotent stem cells for treatment of malignant brain tumors. Stem Cells International. 2016:4095072
  35. 35. Jung JH, Kim AA, Chang DY, Park YR, Suh-Kim H, Kim SS. Three-dimensional assessment of bystander effects of mesenchymal stem cells carrying a cytosine deaminase gene on glioma cells. American Journal of Cancer Research. 2015;5:2686-2696
  36. 36. Lee EX, Lam DH, Wu C, Yang J, Tham CK, Ng WH, Wang S. Glioma gene therapy using induced pluripotent stem cell derived neural stem cells. Molecular Pharmaceutics. 2011;8:1515-1524
  37. 37. Luo Y, Zhu D, Lam DH, Huang J, Tang Y, Luo X, Wang SA. Double-switch cell fusion-inducible transgene expression system for neural stem cell-based antiglioma gene therapy. Stem Cells International. 2015;2015:649080
  38. 38. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M. Autologous induced stem-cell-derived retinal cells for macular degeneration. The New England Journal of Medicine. 2017;376:1038-1046
  39. 39. Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, Nabors LB, Markiewicz M, Lakeman AD, Palmer CA, Parker JN, Whitley RJ, Gillespie GY. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Molecular Therapy. 2009;17:199-207
  40. 40. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Palmer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: Results of a phase I trial. Gene Therapy. 2000;7:867-874
  41. 41. Miletic H, Fischer YH, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H, Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacob AH, von Laer D. Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Molecular Therapy. 2007;15:1373-1381
  42. 42. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nature Medicine. 1995;1:938-943
  43. 43. Morris DG, Feng X, DiFrancesco LM, Fonseca K, Forsyth PA, Paterson AH, Coffey MC, Thompson B. REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Investigational New Drugs. 2013;31:696-706
  44. 44. Myers R, Harvey M, Kaufmann TJ, Greiner SM, Krempski JW, Raffel C, Shelton SE, Soeffker D, Zollman P, Federspiel MJ, Blanco M, Galanis E. Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Human Gene Therapy. 2008;19:690-698
  45. 45. Müller FJ, Snyder EY, Loring JF. Gene therapy: Can neural stem cells deliver? Nature Reviews. Neuroscience. 2006;7:75-84
  46. 46. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoin T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology. 2008;26:101-106
  47. 47. Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, Bizen A, Honmou O, Niitsu Y, Hamada H. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Therapy. 2004;11:1155-1164
  48. 48. Okano H, Yamanaka S. iPS cell technologies: Significance and applications to CNS regeneration and disease. Molecular Brain. 2014;7:22
  49. 49. Okita K, Ichisaka T, Yamanaka S. Generation of germ-line competent induced pluripotent stem cells. Nature. 2007;448:313-317
  50. 50. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322:949-953
  51. 51. Ostertag D, Amundson KK, Lopez Espinoza F, Martin B, Buckley T, Galvão da Silva AP, Lin AH, Valenta DT, Perez OD, Ibañez CE, Chen CI, Pettersson PL, Burnett R, Daublebsky V, Hlavaty J, Gunzburg W, Kasahara N, Gruber HE, Jolly DJ, Robbins JM. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro-Oncology. 2012;14:145-159
  52. 52. Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, Harland J, Mabbs R, Brown M. The potential for efficacy of the modified (ICP 34.5(−)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: A proof of principle study. Gene Therapy. 2002;9:398-406
  53. 53. Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:2208-2213
  54. 54. Price DL, Lin SF, Han Z, Simpson G, Coffin RS, Wong J, Li S, Fong Y, Wong RJ. Oncolysis using herpes simplex virus type 1 engineered to express cytosine deaminase and a fusogenic glycoprotein for head and neck squamous cell carcinoma. Archives of Otolaryngology—Head & Neck Surgery. 2010;136:151-158
  55. 55. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, Petty R, MacLean A, Harland J, McKie E, Mabbs R, Brown M. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Therapy. 2000;7:859-866
  56. 56. Rainov NA. Phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Human Gene Therapy. 2000;11:2389401
  57. 57. Rigg A, Sikora K. Genetic prodrug activation therapy. Molecular Medicine Today. 1997;3:359-366
  58. 58. Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R, Shah K. Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:4822-4827
  59. 59. Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, Lanza R. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet. 2012;379:713-720
  60. 60. Senzer JJ, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. Journal of Clinical Oncology. 2009;27:5763-5771
  61. 61. Stagg J, Lejeune L, Paquin A, Galipeau J. Marrow stromal cells for interleukin-2 delivery in cancer immunotherapy. Human Gene Therapy. 2004;15:597-608
  62. 62. Stuckey DW, Shah K. Stem cell-based therapies for cancer treatment: Separating hope from hype. Nature Reviews. Cancer. 2014;14:683-691
  63. 63. Stupp R, Brada M, van den Bent MJ, Tonn JC. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2014;25:93-101
  64. 64. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005;352:987-996
  65. 65. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872
  66. 66. Takahashi Y, Tsuji O, Kumagai G, Hara CM, Okano HJ, Miyawaki A, Toyama Y, Okano H, Nakamura M. Comparative study of methods for administering neural stem/progenitor cells to treat spinal cord injury in mice. Cell Transplantation. 2011;20:727-739
  67. 67. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676
  68. 68. Tyler MA, Ulasov IV, Sonabend AM, Nandi S, Han Y, Marler S, Roth J, Lesniak MS. Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Therapy. 2009;16:262-278
  69. 69. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E, Certoux JM, Robinet E, Saas P, Petracca B, Juttner C, Reynolds CW, Longo DL, Hervé P, Cahn JY. Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood. 2001;97:63-72
  70. 70. Todo T. Oncolytic virus therapy using genetically engineered herpes simplex viruses. Frontiers in Bioscience. 2008;13:2060-2064
  71. 71. Todo T, Martuza RL, Dallman MJ, Rabkin SD. In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity. Cancer Research. 2001;61:153-161
  72. 72. Todo T, Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:6396-6401
  73. 73. Uzzaman M, Keller G, Germano IM. In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas. Neuro-Oncology. 2009;11:102-108
  74. 74. Wakabayashi T. Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Human Gene Therapy. 2004;15:77-86
  75. 75. Yamaza T, Ren G, Akiyama K, Chen C, Shi Y, Shi S. Mouse mandible contains distinctive mesenchymal stem cells. Journal of Dental Research. 2011;90:317-324
  76. 76. Yoshida J, Mizuno M, Fujii M, Kajita Y, Nakahara N, Hatano M, Saito R, Nobayashi M, Wakabayashi T. Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Human Gene Therapy. 2004;15:77-86
  77. 77. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324:797-801
  78. 78. Yuan X, Hu J, Belladonna ML, Black KL, Yu JS. Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma. Cancer Research. 2006;66:2630-2638
  79. 79. Zhang Z, Jiang Q, Jiang F, Ding G, Zhang R, Wang L, Zhang L, Robin AM, Katakowski M, Chopp M. In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. NeuroImage. 2004;23:281-287
  80. 80. Zhu D, Deng X, Spee C, Sonoda S, Hsieh CL, Barron E, Pera M, Hinton DR. Polarized secretion of PEDF from human embryonic stem cell-derived RPE promotes retinal progenitor cell survival. Investigative Ophthalmology & Visual Science. 2011;52:1573-1585

Written By

Ryota Tamura and Masahiro Toda

Submitted: 16 October 2017 Reviewed: 15 November 2017 Published: 20 December 2017