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Oncolytic Viruses
An overview of current process in Oncolytic virus cancer therapy
| Question | Answer |
|---|---|
| Intro | A virus that selectively replicates in dividing (cancer) cells but cannot replicate in quiescent normal cells. Replication cycle involves a lytic stage which kills dividing cells releasing progeny virus which go on to infect only dividing cells. |
| Intro 2 | Cycle of infection, lysis and progeny release will continue as long as there are dividing cells for the progeny to infect. This means that the therapy is SELF-LIMITING |
| Intro 3 | Always an attenuated virus that has had essential genes removed so that it can not longer infect normal cells but can still replicate and kill cancer cells. 1 in 3 people will get cancer, 1 in 4 die from cancer. |
| Current cancer treatments | Surgery Chemotherapy Radiotherapy Immunotherapy (cancer vaccines, reprogrammed T cells) Oncology predicted to be the biggest pharmaceutical market in 2016 |
| Hepatocellular Carcinoma | 5th most common malignancy 3rd leading cause of death due to cancer 662,000 deaths annually Often caused by viral hepatitis 90% mortality rate within 6 months Virttu HSV-1 ICP34.5 deletion - HSV1716 |
| History of Oncolytic viruses | Dock 1904 noticed remissions in cancer patients when infected with an unknown viral infection. A number of years later a researcher inocculated cancer patients with attenuated Rabis virus and also saw remissions in their cancer. |
| History of Oncolytic viruses problems | adverse effects of infecting with multiple viruses advent of effective chemotherapy |
| Features required for oncolytic viral therapy 1 | Induce cell death by mechanisms other than apoptosis, can insert transgenes which cause cell death by a number of mechanisms. - Decreased resistance in tumours |
| Features required for oncolytic viral therapy 2 | Replicate within tumours to multiply viral dose - amplification leads to further lysis of tumour cells - increases therapeutic index |
| Features required for oncolytic viral therapy 3 | Naturally replicate or are engineered to replicate specifically in tumour cells - minimises normal cell toxicity |
| Engineered oncolytic viruses - Adenovirus | E1A or E1B - produced in high titres, no risk of DNA mutagenesis, can transduce a number of different cell types |
| Engineered oncolytic viruses - Vaccinia virus | TK or Vgf - High transduction, resistant to complement and antibodies, antiviral agents available |
| Engineered oncolytic viruses - Herpes simplex virus - 1 | TK or RR - high yields low antigen loads, easy to manipulate, does not integrate with host DNA, antivirals available E.g. Acyclovir |
| Natural oncolytic viruses | Measles Polio Myxoma +others |
| Interferons | Secreted ligands that bind to receptors on the surface of neighboring cells inducing a signal cascade through the JAK/STAT pathway which activates a number of antiviral genes and immunomodulatory proteins |
| Type 1 interferons | induced in all cell types upon viral recognition Alpha and Beta - induce viral resistance |
| Type 2 interferons | induced by cytokines such as IL-12, expression restricted to NK and T cells Gamma - |
| Type 3 | Lambda, expressed by all cells |
| Cancer cells lose IFN responsiveness | Oncolytic viruses replicate in cancer cells which have lost their IFN response. IFN stimulates PKR |
| PKR | Induces proinflammatory, apoptotic and antiviral response, blocks phosphorlation of eif2a RAS always active in cancer cells - blocks PKR |
| HSV-1 Wild type in normal tissue | In wild type, viral protein ICP34.5 binds to protein phosphotase 1a resulting in dephosphorylation of eif-2a and allowing translation to proceed |
| HSV1716 in normal tissues | ICP34.5 deleted, no binding to protein phosphotase 1a, PKR phosphorylates eif2a preventing translation |
| HSV1716 in cancer tissues | RAB is constantly active, resulting in downstream expression of MEK1/2, suppressing the function of PKR, PKR does not phosphorylate eif2a, allowing translation of viral transcripts to proceed |
| Advantages of HSV-1 | multimeric mechanism of action possibility of DNA transgenes broad biodistribution of receptors antiviral agents |
| Disadvantage of HSV-1 | Can go into a latent state within tumoir cells, not carrying out lytic cycle |
| Immune response to tumours | There can be a systematic anti-tumour response by the immune system through recognition of tumour antigens. mounts a cytotoxic t cell repsonse. |
| HSV1716 and the immune system | HSV1716 has been shown to require immune system for its mode of action - no antitumour effect in immunocompromised mice HSV1716 induces cytotoxic and proliferative t cell anti tumour responses |
| T-VEC | -selectively replicates in tumour cells -generates GM-CSF -tumour cells rupture, GM-CSF released and tumour antigens released -GM-CSF recruits dendritic cells to the site -dendritic cells process and present TSA to specific immune response |
| Balance immune response - negatives | rapid viral clearance reduction in viral replication minimises direct tumour lysis by oncolytic virus REDUCED THERAPY |
| Balance immune response - positives | cytokines/effector cells can help clear tumour cells |
| Barriers to optimum delivery 1 | -absorption by the liver -neutralizing antibodies removing virus from circulation -complement binding and removal of virus -blood cell absorption of virus |
| Barrier to optimum delivery 2 | innate immune system can block spread of virus through a tumour by the IFN responses activating anti-viral state in neighboring cells - proginey fail to replicate. Matrix can form around tumour preventing viral access |
| Possible solutions | modify the virus to encode matrix degrading enzymes. modify the virus to evade the immune system or use immunosuppressive drugs in conjunction with OV therapy |
| Suggested modification using GADD34 | GADD34 has structural homolgy to ICP34.5 and is encoded by host cells. chemotherapy or radiotherapy to induce upgregulation of GADD34 may increase viral replication within tumour cells |
| virus directed enzyme prodrug therapy | use an oncolytic virus to encode an enzyme which activates a prodrug only in cancer cells use an oncolytic virus to encode a transporter protein which allows uptake of drug only in cancer cells |
Created by:
teemo616
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