M7L3 Oncolytic vaccines

  • Difficult to treat human tumours consist of multiple cancer cell ‘nests’ surrounded by stromal fibroblasts

  • Virus mediated lysis is highly immunogenic which attracts/activates T cells

  • Sometimes OVs have demonstrated good activity in clinic but oly when injected intratumorally

  • Cells have evolved to detect virus entry (TLRs, RIG-I, AIM-2, MAVs) which triggers antiviral response (INFx. PKR, STING, mTOR) - shitting down protein synthesis and cell division/DNA replication, activating cell death, alert immune cells to attack and warn neighbours to defend themselves

  • Virus express genes that fights for control of cell and overrides defences

    • Adenovirus genes: E1A activates cell cycle, E1B resists death, E4 (ORF1-6) increases protein production by dysregulating cellular energetics and inhibits DNA damage sensing/repair, E3 avoids immune destruction (downregulates HLA), E28 promotes DNA replication

    • Hallmarks of virus infection are aligned with hallmarks of cancer - conducive for infecting tumour cells

  • OV design - takes out some of the genes (eg E3) to prevent infecting normal cells but can still replicate in cancer cells which have impaired antiviral defences in exchange for promoting tumorigenesis

  • OVs kill in different ways - lysis, apoptosis, oncosis

    • Apoptosis may the ‘worst’ way to kill a cancer cell - immunologically ‘quiet’ pathway or even immunosuppressive

    • Lytic death is very immunogenic by releasing DAMPs —> activates APCs, stimulates T cells, reverses immunosuppression

  • OVs can be armed to increase therapeutic impact - cytokines, antibodies, imaging agents etc

  • Bispecific T cell engagers (BiTEs) - activate t cells via CD3 independent of MHC/TCR, can be encoded within EnAD and secreted from infected tumour cells

    • BiTEs secreted into TME should activate intratumoural T cells to kill chosen target cells

  • Cancer cells are often embedded in a blanjket of fibroblasts - OVs kill fibroblasts and BiTEs may target fibroblasts to kill them locally (circumvents problem of being unable to target fibroblasts due to their presence and thus potential of off target effects all through the body)

  • Why do OVs fail to impress in clinics?

    • Patients have experienced rounds of treatment/radiation and are more fragile

    • Most OVs are immediately neutralised in the blood - persistent perception of failure, little understanding of PK and dose scheduling, retreat to IT delivery disinterest from pharma/investors

    • Manufacturing challenge - RNA viruses mutate rapidly and drift during manufacture while enveloped viruses are low titre fragile, hard to purify and contain components from the packaging cell

    • Desire to deisgn viruses from basic principles - billions of potential OV genomes but only looked at dozen over 20 years, success measured via cell line/mouse models

    • Can not cross stromal barriers