Cell and gene therapy in neuro-oncology

Abstract

The majority of primary brain tumors are gliomas, among which glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 18-24 months, and despite extensive research it remains incurable, thus novel therapies are urgently needed. The current standard of care is a combination of surgery, radiation, and chemotherapy, but still remains ineffective due to the invasive nature and high recurrence of gliomas. Gene therapy is a versatile treatment strategy investigated for multiple tumor types including GBM. In gene therapy, a variety of vectors are employed to deliver genes designed for different antitumoral effects. Also, over the past decades, stem cell biology has provided a new approach to cancer therapies. Stem cells can be used as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. Stem cell-based therapy allows targeted therapy that spares healthy brain tissue as well as establishes a long-term antitumor response by stimulating the immune system and delivering prodrug, metabolizing genes, or even oncolytic viruses. This chapter describes the latest developments and the current trends in gene and cell-based therapy against GBM from both preclinical and clinical perspectives, including different gene therapy delivery systems, molecular targets, and stem cell therapies.

Keywords: Gene therapy; Glioblastoma; High-grade glioma; Nanoparticles; Stem cells; Viral vectors.

Figure 1.. Clinical approaches to treat gliomas using gene therapy vectors and stem cells.

Viral vectors are the most common tool for gene therapy. Viral vectors include vectors derived from Adenovirus (AdV), Herpes virus (HSV), Retrovirus, Newcastle diseases virus (NDV) and Measles virus(MV). Non viral vectors include nanoparticles, liposome and stem cells. The stem cells employed in glioma therapy are neural stem cells (NSC) or mesenchymal stem cells (MSC). One of the most common therapeutic techniques employed in gene therapy is suicide therapy. This involves a system of enzyme plus prodrug: (1) Expression of herpes simplex virus-thymidine kinase (HSV-TK), plus ganciclovir (GCV) treatment, (2) Expression of cytosine deaminase (CD), plus 5-flucytosine (5-FC), (3) Expression of rabbit carboxylesterase, plus irinotecan. Suicide therapy has been explored with both viral and non viral vectors. Other therapeutic transgene used are immune modulators such as Flt3L and IL-12; tumor suppressor target, like wild type p53, or chimeric antigen receptors to be expressed in CAR-T cells, including EGFRvIII, CD1322, Her-2. There is also oncolytic viral therapy which used oncolytic virus (AdV, HSV-1, NM and NDV) can identify, infect, and lyse different cells. Also, MSC and NSC have been used to deliver oncolytic virus.