Oncolytic immunotherapy

Question 1

What is the history of oncolytic immunotherapy?

Answer 1

Sometimes patients with cancer have tumour-regression when they have a viral infection or treated with live-virus vaccine (already 1900-1910). Idea was picked up after WWII and people were treated with live viruses (not very successful). Further development followed in 1980s.

Question 2

Why could oncolytic viruses be a good idea?

Answer 2

The hallmarks of cancer have many similarities with the hallmarks of viral infection. Viruses target cellular pathways that are often mutated in cancer cells.

Question 3

How do you design an oncolytic (adeno)virus?

Answer 3

Oncolytic (adeno)virus design:

1. Tumour-selective expression of essential gene. E.g. Insert a tumour-selective promotor
2. Exploit genetic defects in cancer cells. Mutate the gene so that it cannot replicate in a healthy cell, but can in a cancer cell

Question 4

What is the concept of oncolytic viruses?

Answer 4

A viral agent that can only replicate in cancer cells. In this way normal cells are spared, while cancer cells are killed. When cancer cells are killed by the virus, the virus can spread to other (cancer) cells

Question 5

What is the clinical experience with oncolytic viruses?

Answer 5

Clinical experience with oncolytic viruses:
• Safe
• Signs of clinical efficacy
• Not as effective as in preclinical research
• Best results as part of combination treatment

Question 6

When were oncolytic viruses tested in clinic and what were the results?

Answer 6

They were tested in 2000. They tested intratumoral injection in combination with systemic chemotherapy. Responses were observed in virus-injected tumours and non-injected tumours near the injected tumours.

Keep in mind that this only proves that the combination of oncolytic viruses and chemotherapy is effective!

Question 7

What improvements of oncolytic therapy are studied now?

Answer 7

Increasing infection efficiency, enhancing spread in tumour tissue, improving delivery methods and augmenting cancer cell killing potency (transgenes, mutants),

Question 8

How can the infection efficiency of oncolytic viruses be improved?

Answer 8

Modifying the viral capsid

Question 9

How can the spread in tumour tissue of oncolytic viruses be enhanced?

Answer 9

Enhancing spread in tumour tissue of oncolytic viruses
o Tactic depends on structure of tumour (loose vs. compact)
o Encode gene into viral genome that enhances the spread:
 Decorin
• Remodels the expression of extracellular matrix protein to create more space for the virus to move in between cells
 Hyaluronidase
 Relaxin
 Fusogenic proteins

Question 10

How can delivering methods of oncolytic viruses be improved?

Answer 10

Delivering methods of oncolytic viruses can be improved using (mesenchymal stem) cells as delivery vehicles. This resolves downside of otherwise more effective method of injecting the virus into the blood stream: filtering of the virus by the liver and the immune response against the virus. Cells can extravasate, which is more difficult for the virus

Question 11

How can you augment cancer cell killing potency of oncolytic viruses?

Answer 11

o Mutagenesis
 cloning in genes
o Bioselection
 Culturing the virus while adding compound that induces mutations. You then get a mixture of different mutated viruses. Inject these virusses into tumour-bearing mice. Monitor the tumour growth, take the tumour that has regressed the most and isolate the virus from this tumour. Purify it, culture it and repeat the steps above for 3 cycles. Characterize mutation and clone this back into the original virus to prevent other bad mutation in selected virus genome to influence the treatment.

Question 12

What is the primary effect of virotherapy with an oncolytic (adeno)virus?

Answer 12

o Cell lysis during virus replication

o Amplyfication: progeny virus kills more cells

Question 13

What is the secondary effect of virotherapy with an oncolytic (adeno)virus?

Answer 13

o Lysis releases tumour antigens and the virus acts as an adjuvant (danger signals), hence virotherapy is a form of immunotherapy.

Proven in a semi-permissive hamster tumour model:
 Adenovirus treatment has a direct tumour growth inhibitory effect (lysis+immune system)
Adenovirus treatment protects against tumour growth (immune system)
Arming adenovirus with a cytokine had extra effect (immune system) –> memory response?

Question 14

Are oncolytic viruses considered cancer immunotherapeutics?

Answer 14

Yes

Question 15

Can oncolytic viruses be considered a vaccine?

Answer 15

Yes. It is an autologous in vivo “vaccine”. Vaccine: biological preperation that provides active acquired immunity to a disease. A typical vaccine contains antigens that resemble the disease-causing agent. In the case of oncolytic viruses, anti-cancer antigens are provided by the host cell –> You don’t even have to know the tumour-epitopes

Question 16

Has the efficacy been confirmed in research?

Answer 16

Yes. It has been confirmed that:
• Treatment with oncolytic adenovirus induces infiltration of immune cells
• Damage associated molecular patterns are released from oncolytic adenovirus-infected glioma stem cell-like cells
• Oncolytic adenovirus counteracts immune suppression in melanoma-immune cell co-cultures

Question 17

Should you deplete T-cells to stop the anti-viral response?

Answer 17

No. T-cell depletion increases virus replication and viral load, but decreases cell death and tumour growth inhibition. So, T-cell depletion is not usefull. The T-cells are too important. The clinical success of oncolytic virus treatment correlates with (funtional) T-cell numbers in the tumour

Question 18

With which checkpoint-inhibitors can oncolytic viruses be combined?

Answer 18

• Anti-CTLA-4: To improve antigen cross-presentation
• Anti-PD-1/PD-L1: To overcome immune escape in the tumour microenvironment
o Clinical trial oncolytic virus and anti-PD-1 Ab in metastatic melanoma:
 Oncolytic virus promotes intratumoural T-cell infiltration, but they had increased PD1 and PDL1 expression –> combine treatment with anti-PD-1 antibodies.
 Results: overall response rate 62%, complete reponse rate: 33%. This is a higher response rate then the virus alone

Question 19

What can you use to arm the virus?

Answer 19

With an immune stimulatory transgene:
• Cytokines and chemokines
• Bispecific T-cell engagers
• Immune checkpoint inhibitors
• Etc.

This is the current interest