Oncolytic Virotherapy Development for Brain Tumors (GLIOMA)
Glioblastoma Multiforme (GBM) is a quickly progressing brain tumor with a median survival of less than 15 months. Although cancer patients with glioma diagnoses are relatively low, recent evidence shows that the number of glioma patients have improved over the past decade. Currently, therapeutic strategies for glioma patients comprise tumor resection, chemotherapy, and concomitant radiation therapy. However, radiotherapy and chemotherapy regimens have failed to significantly benefit high-grade tumor patients, and they also are involved in severe long-term side effects that worsen the quality of life. Therefore, the rapid progression of glioma has promoted the development of novel treatment options, including cancer gene therapy and oncolytic virotherapy.
Oncolytic Viruses (OVs) are replication-competent viruses that selectively infect and replicate in cancer cells harboring a multitude of genetic alterations that enables virus propagation. Benefiting from the ample experience in immunotherapy, Creative Biolabs has established an advanced OncoVirapy™ platform. We offer a full range of specific oncolytic virotherapy strategies for glioma, as well as provide OVs construction and validation services to meet every customer's requirements.
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Fig 1. Schematic diagram of the basic mechanism of conditionally replicative adenoviruses vectors (CRAds) mediated cell killing starting with binding of a CRAd particle to a tumor-specific cell surface receptor(s). (Ulasov, I. V., 2014)
Oncolytic Viruses for Glioma
To date, the biggest challenging of malignancies remains to be glioma, because of its unique features, the Blood–Brain Barrier (BBB) and a locally immunosuppressive environment. Considering these limitations, OVs allow to infect and kill glioma, with evidence that they may improve the efficacy of current standard therapy. Currently, OV mediated glioma therapy is deployed intratumorally. A variety of OVs have been studied for the glioma treatment, including Herpes simplex virus type 1 (HSV-1), Adenovirus, Poliovirus, Paramyxovirus, Poxviruses, Parvovirus, and Reovirus. Besides, the growing body of knowledge on signaling pathways activated in glioma cells provides an essential insight into possible molecular strategies for enhancing antitumor efficacy for OV. Genetic analysis of clinical samples exhibited aberrations in the EGFR, PTEN, p16INK4A, and P53 signaling pathways. Approximately 80% of glioblastoma specimens measured in The Cancer Genome Atlas (TCGA) comprise aberrations in CDKN2A and Rb pathways.
Combination Therapy
Despite chemotherapy is a mainstay of current therapy for Malignant Glioma (MG), combined application with OVs may be more effective. Chemotherapeutic drugs enable to address the barriers to effective OV therapy. A number of chemotherapeutics result in cellular and DNA damage that synergizes with the effect of OVs, arresting the cell cycle at multiple points and enhancing apoptosis. Moreover, chemotherapeutic agents temporarily suppress innate immunity, which offers a window of opportunity for viral infection, replication and spread. Adenovirus (Ad) has a similarly positive interaction with Temozolomide (TMZ) and cisplatin. In one case, researchers demonstrated complete tumor regression in 33% of combination therapy of Ad and TMZ. In another clinical study, Liikanen et al. treated refractory cancer patients with oncolytic Ad and low-dose TMZ (100 mg/day) and CPA (50 mg/day). Treated patients were observed to have cytokine release, viral replication, improved autophagy and circulating specific antibodies.
With the rapid progress of novel therapeutic strategies in glioma, OVs continue to hold promise as an effective treatment. Based on our advanced OncoVirapy™ platform, Creative Biolabs is confident in providing novel OVs and developing more efficient oncolytic virotherapy strategies for our customers.
Reference:
- Ulasov, I. V., (2014). "Oncolytic adenoviruses: a thorny path to glioma cure." Genes & diseases, 1(2), 214-226.
- Spencer, D. A., (2015). "Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy." Therapeutic delivery, 6(4), 453-468.