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Oncolytic Viruses “Onco” = cancer “Lytic” = killing An innovative cancer therapy that seeks to harness the natural properties of viruses to aid in the fight against cancer. These non-human viruses replicate in cancer cells and leave normal cells largely unaffected. Clinical data indicates that oncolytic viruses have a very high therapeutic index, in some instances 100000:1. This therapeutic index is significantly higher than the index commonly seen in chemotherapy - 6:1- and may result in greater efficacy with fewer side effects. Scientific American October 2003 A Historical Perspective on Therapeutic Viruses Early human trials using viruses in anti-cancer treatments initially yielded excitement as tumor regression was often seen without toxicity; however, tumor regression was followed by tumor progression during the late stages of these trials. As a result of these early clinical trials, the idea of using viral vectors diminished in the hopes that a better understanding of cancer biology would allow for the development of more effective approaches. Recently there has been a renewed interest and optimism in virotherapy with the convergence of ideas from molecular oncology and virology, and the development of recombinant virus technologies. Vesicular Stomatitis Virus VSV is not a human pathogen and thus the host lacks neutralizing antibody against the virus. VSV generally causes mild, non-fatal disease in cattle and swine. The inability of VSV to cause mortality in animals or humans is a result of its sensitivity to the host antiviral response - a response that appears defective in cancer cells. VSV is an attractive candidate as a viral delivery system for a variety of reasons: 1. VSV is easily manipulated by recombinant techniques. 2. VSV can be grown to very high titers (1010 pfu/ml) 3. VSV is non-pathogenic in humans. Morphology and Genomic Organization of Vesicular Stomatitis Virus 45 -100 nm Glycoprotein (G) 100 - 430 nm Nucleocapsid (N) Matrix (M) Large Polymerase (L) Phosphoprotein (P) Nucleocapsid (N) Matrix (M) Phosphoprotein (P) Glycoprotein (G) Large (L) Polymerase VSV Oncolytic Activity Targets Many Different Tumor Types Breast tumour-derived cells and tissue Ovarian carcinoma Prostate cancer Melanoma Colon carcinoma Lung tumour-derived cells and tissues Why is VSV Oncolytic? Although it has been known for some time that VSV selectively infects and kills transformed cells, the mechanism has remained unknown. Normal Cell IFN AntiViral Response Transformed Cell IFN AntiViral Response X The IFN response system is disrupted in transformed cells, thus permitting selective VSV oncolytic activity, while sparing normal non-transformed cells. Eradication of CT26 Lung Metastases Following Intravenous or Intranasal VSV Inoculation VSV GFP time course in CT26 lung metastasis model 12 8 hours 0 11 12 hours 27 hours 24 72 hours 72 5x108 VSV GFP + 5x108 VSV RFP 12hr VSV in Action: Imaging Oncolysis Conclusions VSV is an excellent candidate oncolytic virus with a broad range of anti tumor effects Attenuated VSV strains with mutations in the viral matrix protein fail to block the development of innate immunity and provide a better therapeutic virus Curing cancer in mice is easy …….. the challenge is to determine the efficacy of several different oncolytic viruses in a variety of human tumors Oncolytic Viruses in Clinical Trials Name Strain 1. Onyx-015 Ad2/5 Alterations ∆E1B-55kD Mechanism p53 deficient Disease Head/Neck Cancer Ovarian, Liver Pancreatic Cancer Phase II-III I-II I 2. CV706 Ad5 ∆E3 Deletion Oncolysis of PSA Prostate Cancer E1A-PSA promoter expressing cells I-II 3. G207 HSV-1 ∆ g145.5 deletion Removal of viral Malignant glioma counter-attack I-II GM-CSF Insertion Immune Recruitment Melanoma I-II 4. V/GM-CSF VV 5. Reo Reovirus Naturally Attenuated Ras/PKR Defects Advanced solid Tumors I-II 6. VSV AV1 IFN Defects Advanced solid Tumors I Naturally Attenuated