**Stem Cell Research for the Treatment of Malignant Glioma Glioma**

**Stem Cell Research for the Treatment of Malignant** 

DOI: 10.5772/intechopen.72504

Ryota Tamura and Masahiro Toda

Ryota Tamura and Masahiro Toda Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72504

#### **Abstract**

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.

**Keywords:** 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].

#### Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

**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. Replicationcompetent 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.

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

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.

IL-2, IL-4, IL-12, IL-18, GM-CSF, IFN-γ, B7-1, and

Stem Cell Research for the Treatment of Malignant Glioma

http://dx.doi.org/10.5772/intechopen.72504

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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

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

TGF-β antisense

inactivation of UL39

Suicide gene/prodrug • HSVtk/ganciclovirl • CD/5-flucytosine

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

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

and ability of the immune response against glioma cells [53, 71, 74].

**Gene therapy Characteristics Types**

immune response.

surrounding tumor cells.

apoptosis of tumor cells.

**Table 1.** Characteristics of gene therapies.

Cytokine based therapy can increase the proliferation of cytotoxic T cells and natural killer cells, enhancing anticancer

Suicide genes can change a nontoxic prodrug into a toxic substance that triggers

Genetically modified oncolytic viral vectors can selectively replicate in tumor cells. Viral particles are released and spread to

Cytokine based therapy

Oncolytic virus therapy

Suicide gene therapy

[11, 33, 44, 76].

**2.2. Oncolytic virus therapy**

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**).
