Oncolytic viruses  

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dumbcritic
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02/11/2018 11:05 pm  

It's been known for a number of years that certain oncolytic viruses can target both bulk cancer cells as well as CSCs. Engineering in interleukin 12 in one of them produced a significant but modest improvement in survival http://www.pnas.org/content/110/29/12006.long Immune checkpoint inhibitor antibodies alone (either anti-PD-1 or anti-CTLA-4) produced only modest improvement in survival, similar to the virus, while the combination of virus with either antibody further extended survival. However, the triple combination cured ~90% of mice and protected them from re-challenge http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30298-2

Now a Phase I trial using the virus alone is ongoing https://clinicaltrials.gov/ct2/show/NCT02062827


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dumbcritic
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02/11/2018 11:06 pm  
Another trial testing an oncolytic virus is recruiting in the UK https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004548-12/GB
 
They tested a number of HSV strains and selected the most effective. Preferential replication within cancer cells is due to the deletion of certain genes like ICP34.5 https://www.nature.com/articles/3301885 This is aided by the availability of a pool of nucleic acids and many have disrupted anti-viral responses (defects in interferon and PKR signaling).
 
It expresses GM-CSF and a fusogenic protein (GALV) as well. The latter increase immunogenic cell death http://cancerres.aacrjournals.org/content/60/6/1492.long http://cancerres.aacrjournals.org/content/62/22/6566 Deletion of another gene (ICP47) helps to facilitate antigen presentation and promotes an antitumour immune response. Antiviral effects also help with this too https://www.cell.com/trends/immunology/fulltext/S1471-4906(17)30228-4

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Jcancom
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02/11/2018 11:30 pm  

critic, what I have been wondering about lately is what would happen if an oncolytic virus were packaged in chitosan? If there were a way to make the virus invisible to the immune system then you could have even better responses. With oncolytic viruses, the treatment can amplify inside the body. This is such a powerful feature of the. The problem is that the immune system is always trying to fight the virus. Getting the virus to the tumor without detection would seem a great strategy.


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dumbcritic
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03/11/2018 12:11 am  

One company is working on this https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0277-7  https://clinicaltrials.gov/ct2/show/NCT02636036

Other routes that could be investigated further are locoregional (e.g., via the hepatic vein), intrapleural and inhalation https://www.spandidos-publications.com/ijo/31/5/1009 https://www.ncbi.nlm.nih.gov/pubmed/8275514 https://link.springer.com/article/10.1007%2Fs00109-010-0605-6


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Jcancom
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03/11/2018 2:46 am  

critic, I read through the triple combo mouse study. This is very impressive! It is quite remarkable that we have now reached an era in which curative responses might occur if patients simply used existing treatment options. For example, Tvec, anti-CTLA4 and anti-PD1 treatments are now already marketed! I am also interested in how additional products in the pipe might combine. For example, NKTR-214 certainly springs to mind. I will be so relieved when cancer is finally a distant memory.


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Jcancom
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03/11/2018 4:59 am  

critic, what do you think of the idea of metronomic dosing? Many on this forum are excited by this! It is a simple idea though it could be very powerful! Even something as simple as turning on a pump and doing 24/7 dosing with vitamin C could give very large results. The big concern would be that TLS could occur. Shutting off the energy supply of cancer for a prolonged time should lead to a profound energy crisis for the tumor but not normal cells.

 


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Jcancom
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03/11/2018 5:16 pm  

hmm, I had wondered about the anti-body angle of oncolytic viruses. If anti-bodies engage the viruses then what is the point of continuing treatment? Recent research has found this line of thought not to be true.

https://www.oncolyticsbiotech.com/press-releases/detail/432/oncolytics-biotech-announces-a-publication-demonstrating


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dumbcritic
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05/11/2018 9:49 pm  

The abstract for DNX-2401 plus Pembro (NCT02798406) has been published  https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_6/vi6/5153658 and the company are running another PhI (NCT03714334) in Spain testing DNX-2440 (this is 'armed' with OX40L).


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dumbcritic
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05/11/2018 9:56 pm  

It would be nice to see more investigator sponsored trials using this in certain indications. Personally, I think another trial in mPDAs should test gemcitabine, nab-paclitaxel and the virus https://www.nature.com/articles/bjc2013415  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-1037-z If that was safe and showed encouraging signs of activity, then they could move things forward by adding on PEGPH20  https://www.cell.com/cancer-cell/fulltext/S1535-6108(12)00039-6 Upon progression they could be then treated with Opdivo (+/- Yervoy).


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dumbcritic
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05/11/2018 10:02 pm  

I'd follow the Drs. Cameron and Pauling trials and then add on a liposomal version as well as powder https://www.isom.ca/article/vitamin-c-cancer-use-oral-vitamin-c/


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