Viral therapies - oncolytic viruses

• Viral therapies


  Oncolytic viruses
• Revised


  Not started
• Completed


  Summary notes and Questions
• Modalities of cancer treatment

  • Surgery
  • Radiotherapy
  • Chemotherapy
  • Immunotherapy
  • Virotherapies

  
• Viruses


  • Pathogenic and causes damage to tissue but can be used for a range of therapeutic applications if trained
  • Both gene and cellular therapies are the future of medicine and required trained viruses

  
• Therapeutics using viruses


  • Blindness
  • Haemophilia
  • Immunodeficiencies
  • Spinal muscular atrophy
  • Sickle cell anaemia
  • Vaccines
• Oncolytic


  • Retains potency and is highly selective
  • Seeks cancer cells and attracts immune cells to site of cancer

  
• Oncolytic virus candidates


  • Adenovirus
  • Poxviruses
  • Herpes simplex 1
  • Many other DNA and RNA viruses

  
• hCAR


  Ubiquitous, negative correlation with tumour progression
• CD46


  Ubiquitous, dampening of host immune response
• DSG2


  Potential to stimulate EMT
• Developing therapeutic virus


  1. Taming the virus

  2. Training
• Taming the virus


  • Causation of disease
  • Infection mechanism
  • Causation of toxicity
  • Genetic engineering to remove the above problems
• Training


  • Identification of a target on cancer cells for infection
  • Genetic engineering of the virus to use cancer specific markers
  • Coupling with therapeutics

  
• Adenovirus


  Can interact with CAR, Salic acid, desmoglein and CD46. However, these are not biomarkers expressed by cancer cells

  
• Adenovirus type 5


  Can bind to human blood clotting factor which provides a means to spread infection to the liver - rapid and highly efficient
• Penton base


  Can interact with integrins to enter the spleen
• Ad5null


  Basal with no means of infection and therefore no replication
• Tumour selective biomarker


  Engineered into the virus where the biomarker can be recognised and bound by the knob protein

  
• AvB6 integrin


  • Epithelial specific integrin and is expressed on the cell surface
  • Not detectable on normal adult epithelia but is unregulated during development, wound healing and carcinogenesis

  
• A20 peptide


  Found to interact with AvB6 integrin to form a stable and high affinity binding
• Ad5null-A20 virus


  • Does not enter the cells expressing CAR
  • Uses AvB6 for cell entry

  
• EOC004


  • Cancerous cells

  
• Mice with no tumours


  Ad5 virus preferentially entering the liver and having a vast more amount of DNA in the liver compared to Ad5null-A20
• Tumours regressed when treated with Ad5null-A20

  
• Ad5null-A20 localises to tumour sites, Ad5 infects the peritoneal cavity indiscriminately

  
• Treatment with Ad5null-A20 results in 100% survival in an ovarian cancer model

  
• The more AvB6 is present

  The increased infiltration of the Ad5null-A20 in the tumours
• Trocept with ALAG3


  • A truncated version is formed
  • Precision virus directed enzyme prodrug therapy - in tumor chemotherapy
  • Precision immunovirotherapies - in tumour immunotherapy - expression of immune checkpoint inhibitors

  
• Virus is binding to cells expressing LAG3
• Modalities of Cancer treatments

  • Surgery
  • Radiotherapy
  • Chemotherapy
  • Immunotherapy
  • Virotherapies

  
• Viruses


  • Wild type - cause immense destruction and suffering
  • Tamed and Trained virus - they can be forces for immense good for a range of therapeutic applications, including cancer
• Gene Therapies & Cellular Therapies are the future of medicine and commonly require "trained viruses"
• Gene therapies curing


  • Blindness
  • Haemophilia
  • Immunodeficiencies
  • Spinal muscular atrophy
  • Sickle cell disease
  • Vaccines SARSCoV2
• Oncolytic viruses


  • It will kill the cancer- using aggression in a targeted manner to signal the immune cells to the tumour site
  • Retains potency
  • Highly selective
  • Trained to seek and destroy cancer cells only
• Why develop oncolytic viruses to treat cancer?

  • Amplifies within the tumour causing the cell to burst - immunogenic cell death
  • Can encode additional anticancer genes within virus

  
• Oncolytic adenovirus: barriers to success

  • Receptors: hCAR, ubiquitous, negative correlation with tumour progression CD46: ubiquitous, dampening of host immune response; DSG2: potential to stimulate EMT
  • Seroprevalance rates

  
• Oncolytic viruses inducing immunogenic cell death through oncolysis


  1. Oncolytic virus selectively infects tumour cell

  2. Makes copies of itself

  3. Lyses the tumour cells - oncolysis

  4. Oncovirus induces cancer burst - releases antigens

  5. Now DC can come and pick those antigens and prime the T cells

  
• Oncolytic immunotherapy


  Allows Tumour-specific replication and lysis + therapeutic genes + immune activation

  
• Historical development of Viral Cancer Gene Therapy

  • 1990 Non-replicating viruses - delivery of therapeutic genes
  • 2000 Oncolytic viruses - oncolytic biotherapy
  • NOW Oncolytic Immunotherapy