Oncolytic viruses Flashcards
What are the three main goals of oncolytic virotherapy?
- Kill tumor cells directly via viral replication
- Make tumor cells visible to the immune system
- Activate the immune system, recruiting T cells and other immune effectors.
What is the two-step mechanism of action of oncolytic viruses?
Oncolysis: Viral infection, replication and lysis of tumor cells, releasing tumor antigens
Immune activation: Cytokine release and antigen presentation to T cells, amplifying anti-tumor immune response
How are OVs designed for tumor specificity? (3)
Oncotropic viruses exploit conditions in the tumor microenvironment (such as disrupted IFN responses)
Genetically engineered viruses contain deletions or mutations that restrict replication to tumor cells, and can include tumor-specific promoters driving viral replication
Armed viruses encode cytotoxic or immune-stimulating transgenes (such as chemokines to stimulate DC attraction)
What in vitro studies required for OV development?
Assessment of tumor selectivity, toxicity, penetration into 3D solid structures and general effectivity in cell killing
What preclinical in vivo studies are necessary for OV assessment?
- Subcutaneous patient-derived tumor xenograft in immune deficient mouse models (only looks at oncolysis.
- Immune-competent murine xenograft mouse model (looks less at oncolysis but more at the immune system, since the virus is more specific for human tumor cells)
- Organ-specific tumor
- Re-challenge to look at immune memory
What are three crucial components of oncolytic virus safety studies?
- Toxicity assessment of administration
- Biodistribution assessment (to look at leakage into other organs)
- Assessment of excretion for presence and shedding of the virus to ensure modified virus is not leaking into the environment (or if it does, assessment of whether it can mutate to become more virulent or not)
What 5 topics need to be considered for clinical application of oncolytic viruses?
- Delivery method (systemic, local, injections, infusions)
- treatment schedule
- Patient group (primary, recurrent)
- Safety (patients, environment)
- Trial-associated studies (follow-up, samples required)
What strategies are being undertaken to improve OV therapy?
- Combine OV treatment with standard-of-care treatments
- Arming of OVs with cytotoxic genes
- Arming of OVs with immune-stimulatory genes
- Combine with viral enhancing agents
- Combine with immunotherapies (CAR T cells, TCR therapy)
- Arming of OVs with a cDNA library of tumor antigens
- Prime-boost with same or different OVs
- Personalize OV treatment (like what Marco is doing)
What are the three categories of hurdles in oncolytic viruses as therapy?
- Regulatory aspects
- Production
- Biological challenges
What are the 3 main biological challenges with oncolytic virus therapy?
Tumor heterogeneity
Immune response: shift from anti-viral to anti-tumor
Delivery
Why are regulations put in place for OV therapy?
Patient safety and environmental safety
What 4 things are important to achieve when producing oncolytic viruses?
High yields
High purity
Production consistency
Genetic stability
What two hurdles are there regarding genetic stability?
RNA viruses are not as stable as DNA viruses
Transgenes are easily kicked out
How can patient stratification be used in oncolytic viral therapy/trials? (2)
If possible, try to link the molecular profile of a tumor to sensitivity to a particular OV
Pre-screen OVs on primary tumor culture of each patient
What can you do to shift the immune response against the tumor as opposed to the virus in oncolytic therapy?
Modify the virus in such a way that it does not trigger certain PRRs (such as TLR2 which induces antibody production such as in the case of oncolytic vaccinia) but does trigger others that are more important for CD8 T cell activation (such as TLR3)
What is the prime-boost strategy in OV therapy and why is it used?
You want only boosting of anti-tumor T cells and not a mixture of anti-tumor and anti-viral T cells. To prevent this, you can come with a second vector with a different coating the second time around, you preferentially expand and boost the anti-tumor T cells. This leads to a higher number of antigen-specific CD8 T cells with a memory phenotype and higher functionality (cytokines, etc).
What is the main problem with delivery of oncolytic viruses?
In many cases, it is not possible to directly hit the tumors (due to placement or metastases)
How can oncolytic virus delivery be improved if it’s not possible to directly inject into (all) tumors? (2)
Genetic modification of the virus
Coupling of molecules after production (bi-specific antibodies)
What are the two biggest problems with systemic injection of oncolytic viruses?
Most is taken up by the liver
Pre-existing immunity against similar viruses (such as in adenovirus)
How systemic delivery issues be helped? (3)
-Using blood-borne viruses like measles and polio
- Using viruses to which we have no pre-existing immunity (such as Newcastle or non-human type adenovirus)
-Using exosomes as vectors
