Virotherapy,as a key for cancer treatment


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Virotherapy,as a key for cancer treatment

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Virotherapy,as a key for cancer treatment

  1. 1. Cancer is………  Unusual cell growth caused by genetic mutation  Usually in form of tumor  Not all tumors are cancerous. Tumors can be benign or malignant  Benign tumors are not cancerous and can be removed and do not spread through out the body.  A malignant tumor is an aggressive and invasive tumor which has a tendency to grow and spread in the body through the lymphatic system or blood stream.
  2. 2. CANCER TREATMENTS Chemo therapy Nano Technology Surgery Radiation Genetic Engineering
  3. 3. ONCOLYTIC VIRAL THERAPY  Oncolytic Onco: prefix for tumor Lytic: relating to lysis(destruction of cell)  An Oncolytic virus (OV) is a virus having the ability to specifically infect and lyse cancer cells, while leaving normal cells unharmed.  Here, certain viral genes act as tumour destructive agent, and the viral capsid as a nano-sized nucleic acid delivery vehicle.
  4. 4. ONCOLYTIC VIRAL THERAPY  In general, oncolytic viruses derive their specificity by exploiting cell surface receptor or intracellular aberrations in gene expression that arise in malignancies during tumour development.
  5. 5. STRATEGIES FOR TUMOUR TARGETING A. Pro apoptotic targeting B. Transcriptional targeting C. Translational targeting D. Transductional targeting E. Targeting strategies based on tumour microenvironment F. Targeting tumour using carrier cells as cellular vehicle for oncolytic viruses
  6. 6. A. PRO APOPTOTIC TARGETING :  Many viruses delay apoptosis of infected cells in order to assist their replication.  These encode certain proteins which alter the activity of E1 A E1 B important regulators of programmed cell death such as p53 and pRb. pRb p53 Normal cell Delay premature apoptosis
  7. 7. A. PRO APOPTOTIC TARGETING : E1 GENE Normal cell cannot compensate the deleted function Target cancer cell compensates the deleted viral function Virus does not replicate Viral replication and cell death
  8. 8. A. PRO APOPTOTIC TARGETING : Some viral and non viral proteins are known to induce p53 independent apoptosis in tumour cells:  Chicken anaemia virus derived apoptosis – inducing protein (apoptin)  Torque teno virus derived protein TTV apoptosis inducing protein (TAIP),  The human α-lactalbumin made lethal to tumour cells (HAMLET),  Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL),
  9. 9. B. TRANSCRIPTIONAL TARGETING Oncolytic viruses can be rendered tumour selective by placing essential viral gene under the regulation of tumour specific promoter. However, this technique is limited to DNA viruses (excluding pox viruses). For example : Survivin is over expressed in Squamous carcinoma cell which makes it possible to use therapies specifically targeting this gene. Activity of these promoters can be further augmented by binary regulatory system with recombinant Gal 4 fusion protein.
  11. 11. B. TRANSCRIPTIONAL TARGETING VIRUS Adenovirus GENES PROMOTER USED CANCER TYPE Prostate specific antigen (PSA) and probasin promoter Prostate carcinoma E1 A α- foetoprotein promoter Hepatocellular carcinoma E1 A Herpes simplex virus E1 A and E1 B Mucin-1 promoter and estrogen – receptor promoter Breast carcinoma ICP4 gene Albumin enhancer promoter Hepatocellular carcinoma
  12. 12. C. TRANSLATIONAL TARGETING : Tumour specificity is by mutating the oncolytic virus to induce more potent IFN response. This will minimize the replication of such viruses in normal cells but the cancer cells will remain permissive. Also some viruses block IFN signaling by encoding protein which inhibits the translation of mRNA for IFN e.g. matrix (M) protein of vesicular stomatitis virus (VSV). Such viruses can be rendered tumour specific by mutating the genes encoding the protein inhibiting IFN release. The non pathogenic VSVs can still multiply in tumour cells as these lack ability to produce and respond to IFN.
  13. 13. C. TRANSLATIONAL TARGETING : HSV-1 can be made tumour selective by mutating the γ134.5 gene .The product of this gene (ICP34.5) binds with protein phosphatase-1 and inhibits phosphorylation of eukaryokotic initiation factor-2 (eIF-2) by activated PKR (ds RNA induced protein kinase).  This unphosphorylated eIF-2 cannot inhibit translation of viral transcripts unlike its phosphorylated counterpart.  Cancer cells are resistant to the PKR activated inhibition of viral replication due to the high level of Ras activity which inhibits autophosphorylation of PKR. Thus mutant having deleted γ134.5 cannot multiply in normal cells but tumour cells remain permissive.
  15. 15. D.TRANSDUCTIONAL TARGETING : The fact that tumour cells display high level of tumour specific receptors can be exploited for targeting of oncolytic viruses specifically to cancer cells. For instance, many cancer cells over express intra cellular adhesion molecule-1 (ICAM-1) and decay accelerating factor (DAF), the receptors for coxsackievirus A21(CAV21). ICAM 1 DAF CAV 21
  16. 16. D.TRANSDUCTIONAL TARGETING : Enterovirus, echovirus type 1, gains preferential entry to ovarian cancer cells due to over expression of the I domain of integrin α2β1
  17. 17. D.TRANSDUCTIONAL TARGETING : Mumps viruses use sialic acid as their receptor and alpha viruses use heparin sulphate or ICAM-1, all abundantly expressed also on many normal cells, these viruses show high cancer cell selectivity due to defective interferon (IFN) signaling pathway in tumour cells.  Alternatively, tumour specificity of viruses can be reprogrammed by displaying single chain antibodies or other polypeptide binding ligands on the viral surface.
  18. 18. E . TARGETING STRATEGIES BASED ON TUMOUR MICROENVIRONMENT To support uncontrolled growth and tissue invasion, tumour cells develop a modified microenvironment such as hypoxia, activation of certain proteases and angiogenesis. This can be harnessed for developing strategies for tumour targeting.
  19. 19. E . TARGETING STRATEGIES BASED ON TUMOUR MICROENVIRONMENT A dual regulated oncolytic Ad CNHK500 was developed in which the E1b gene is controlled by a hypoxia responsive promoter and the E1a gene is controlled by an human telomerase reverse transcriptase (hTERT) promoter.
  20. 20. F. Targeting tumour using carrier cells as cellular vehicle for oncolytic viruses Cancer cell secretes a number of chemokines which helps in trafficking of immune cells to tumour.  These immune cells can be used as cellular vehicle for efficient delivery of OVs to tumour cells. Other types of cells such as stem cells (mesenchymal, endothelial progenitor cells) have also been developed as cellular vehicles to deliver OVs. The tumour carrier cells can be inactivated by gamma-irradiation after infection with the OV.
  21. 21. ADENOVIRUS: Adenovirus has emerged as one of the most potential viral therapeutic agent in cancer therapy. In the late 1950s, adenoviruses were reported to induce apoptosis in HeLa cells. Since then, clinical trials have begun on different experimental models both in vivo and in vitro. JESSE GELSINGER,
  22. 22. ADENOVIRUS: The adenoviral genome consists of linear, dsDNA of 26-45 kb. It is a non-enveloped, icosahedral virus with capsid of 65-80 nm diameter The structural elements of capsid comprise penton, hexon and fibre proteins which play a crucial role in virus entry into the cells.
  23. 23. ADENOVIRUS:
  24. 24. ADENOVIRUS: In this process, a series of viral proteins co-operate to promote efficient replication of the virus and its release. These major viral proteins include E1A, E1B-55kD, E1B-19kD, E3-11.6 kD and other associated proteins..
  25. 25. G1 Phase E1B S Phase Viral replication E1 A E1B pRb E1 A Apoptosis G1 Phase E1 A E1B S Phase No infection Viral replication and cell death
  26. 26. REOLYSIN REOLYSIN® is a proprietary variant of the reovirus, an acronym for Respiratory Enteric Orphan Virus, which is widely found in the environment. . It was found that the reovirus was able to infect and selectively destroy cancer cells.  When a normal cell is infected with the reovirus, an antiviral response is activated, which prevents the virus from replicating within the cell.  However, inside a cancer cell with one or more mutations on a growth pathway called the Ras pathway, there is an aberrant antiviral response that is unable to prevent the virus from replicating.  This abnormality allows the reovirus to multiply to an extent that is fatal to the cancer cell.
  27. 27. REOLYSIN
  28. 28. REOLYSIN
  29. 29.  Have a large therapeutic index (i.e. high potency against malignant cells) with little or no toxicities to normal cells.  Fewer side effects than other treatments  Treating previously incurable cancers  Greater success rate, survival rate