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Oncolytic Viruses in Astrocytoma Treatment

Astrocytoma is one type of cancers that form in the brain or spinal cord. Astrocytoma develops from astrocytes that support nerve cells. Therefore, astrocytoma belongs to the class of glial tumors. Oncolytic viruses (OVs) are live viruses that are designed to selectively target, infect, and replicate in cancer cells, with minimal destruction of non-neoplastic tissue. Oncolytic virus therapy is a novel treatment option for astrocytoma.

About Astrocytoma

Astrocytoma is the most common glial tumor and that can develop in the brain and spinal cord. There are several types of astrocytomas, broadly classified as either diffusely infiltrating or localized (circumscribed). Localized astrocytomas have a potential of cure following surgical resection because of relatively lower grades. According to WHO classification system for tumors of the central nervous system (CNS), astrocytomas can be classified into four grades: Grade I lesions included pilocytic astrocytoma, grade II consisted of diffuse astrocytoma; grade III of anaplastic astrocytoma, and grade IV of glioblastoma (GBM).

Oncolytic Viruses in Astrocytoma Therapy

Based on astrocytoma, various oncolytic viruses have been used in preclinical and clinical trials to evaluate safety and efficacy. Oncolytic viral therapy for astrocytoma holds great promising with high safety profiles and low off-target toxicities and it will undoubtedly impact the future of patient care. OVs derived from Herpes Simplex Virus-1 (HSV-1), Adenovirus (Ad), New Castle Disease Virus (NDV), and Reovirus (RV) have been reported in several preclinical/clinical trials for the treatment of astrocytoma.

Oncolytic Viruses in Astrocytoma Treatment

HSV-1, belonging to the Herpesviridae family, is an enveloped, double-stranded DNA virus containing a large, well-characterized, fully sequenced genome of about 152 kb of DNA. Oncolytic HSV-1 shows several advantages as a very desirable vector for therapeutic applications: 1) the large size provides ample opportunities to remove genes that are not essential for replication (estimated to be about 30kb) to insert therapeutic transgenes; 2) remaining as an episome avoiding the possibility of any insertional mutagenesis of the infected cell; 3) easy access to manipulation; 4) the easy availability of antiherpetic drugs in order to keep viral replication in check.

Oncolytic Viruses in Astrocytoma Treatment

Ad is a non-enveloped virus containing a 36 kb double-stranded, linear DNA genome. Its genome is divided into early genes (E1A, E1B, E2, E3, and E4) and late genes (L1-L5). Early genes encode corresponding proteins that are expressed early during viral replication whereas late genes are expressed after the commencement of viral replication and encode for capsid proteins. The first recombinant adenovirus (H101) for nasopharyngeal cancer treatment was approved in November 2006 in China. ONYX-015 (dl1520), a conditionally replication-competent adenovirus with a deletion in its 55kDa E1B gene, was created to be replication-competent only in neoplastic cells.

Oncolytic Viruses in Astrocytoma Treatment

NDV is a single-stranded RNA virus that is associated with minimal pathology comprised of mild conjunctivitis and laryngitis in humans. It has been previously described that NDV can directly replicate in and kill a variety of cultured human neuroblastoma cells without effect in normal fibroblasts, amongst, HuJ and MTH-68 strains have been patented for their use as antineoplastic agents.

Oncolytic Viruses in Astrocytoma Treatment

RV is a double-stranded RNA virus, which can efficiently infect most mammalian cells but often causes asymptomatic infection because of cellular antiviral defense responses. However, in neoplastic cells, Ras signaling is activated to permit reovirus to efficiently replicate in proliferating cells. RV acting as an antineoplastic agent has been tested in several animal models of brain tumors, and the results revealed its antineoplastic efficacy.

Oncolytic Virus Virus Genetic Alteration Year Patients M/F (Total) Adverse events Highest Dose Administered Tumor type (n)
G207 HSV-1 (Strain F) Deleted for both the copies of γ34.5 gene and disrupted ICP6/RR. 2000 15/6(21) None 1 × 109 p.f.u. GBM(16) AA(5)
G207 HSV-1 (Strain F) Deleted for both the copies of γ34.5 gene and disrupted ICP6/RR. 2008 6 None 1.15 × 109 GBM
1716 HSV-1 (Glasgow strain 17) Deleted for both the copies of γ34.5 gene 2000 7/2(9) None 1 × 105 p.f.u. GBM(8) AA(1)
1716 HSV-1 (Glasgow strain 17) Deleted for both the copies of γ34.5 gene 2002 7/5(12) None 1 × 105 p.f.u. GBM(8) AA(1)
1716 HSV-1 (Glasgow strain 17) Deleted for both the copies of γ34.5 gene 2004 10/2(12) None 1 × 105 p.f.u. GBM(10) AA(1) AO(1)
ONYX-015 Adenovirus Deleted in its E1B gene 2004 17/7(24) None 1 × 1010 p.f.u. GBM(17) AA(5) Grade 2(2)
NDV-HuJ New Castle Disease virus None 2005 9/5(14) None Up to 55 BIU GBM
Reolysin Reovirus None 2008 7/5(12) None 1 × 109 p.f.u. GBM(7) AA(3) AO(1) OA grade II (1)

Table.1 List of clinical trials treating glioma patients with oncolytic viruses. (Haseley, 2009)

How to Improve OV Specificity and Efficiency?

To design an oncolytic virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long-lasting tumor-specific immunity, various ways have been developed for oncolytic virus engineering. With the development of modern genetic engineering techniques, novel strategies have been discovered to optimize the construction of OVs, to reduce their clinical toxicity, to construct efficient OV delivery platforms, and to increase the efficacy of OVs, with the aim of achieving the greatest therapeutic benefit. For example, to improve OV therapeutic efficacy, we can design viruses which can express cytokines to activate a systemic antitumor immune response, insert angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extracellular matrix (ECM) to enhance viral spread through solid tumors.

Reference

  1. Haseley, A.; et al. Advances in oncolytic virus therapy for glioma. Recent patents on CNS drug discovery. 2009, 4(1): 1-13.

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