I tend to engage in a lot of thought experiments...
Absolutely no one is talking about electroporating checkpoint inhibitors, as they are administered systemically. For metastatic diseases, this wide administration makes a lot of sense, as tumors are found in more than one place in the body.
But what were to happen if you were to electroporate a combination of genes including IL-12 and GP96/OX40L with checkpoint inhibitor(s)?
In non-metastatic solid tumors, I think complimentary pathways would be triggered to allow complete tumor regressions. This would theoretically benefit patients with both resectable and non-resectable tumors. In patients who would normally have tumors surgically removed, you could build immunity to tumor associated antigens, thus preventing recurrences. You tend to see maintenance chemo therapy in patients with surgically removed tumors;this combination EP approach would replace the chemos and would be performed prior to hypothetical surgical removal. I even think surgery will ultimately become unnecessary in most patients - that is how effective I think a combination EP version of IL-12/GP96/OX40L/checkpoint inhibitors would prove to be. I think non-resectable tumors will be dealt the same death blow, leading to long term immunity and recurrence free outcomes.
I even see a situation where the same EP combination could be used in metastatic cancers. I think an electroporated combination of IL-12, GP96/OX40L, and checkpoint inhibitor(s) would serve to immediately annihilate a solid tumor, and using the OX40L co-stimulatory pathway, you would observe significant polyclonal expansion of activated and tumor specific CD8 tcells. The resulting abscopal effect would then serve to prime metastatic tumors for systemic checkpoint inhibitor use.
I seriously believe checkpoint inhibitor genes can be electroporated and expressed intratumorally with other complimentary genes like those I listed. There would still be a reason to use systemic anti-pd-1, anti-ctla-4, and other checkpoint inhibitors in metastatic disease; however, an electroporated version of those genes would become the more universal application.
Obviously, this is what I would personally pursue, not necessarily what Oncosec is going to do. I see substantial synergy between the combination I just mentioned. I can go into great detail about the pathways for each gene element, but I will save that for another post.
On a personal note, I lost my mother 10 years ago from an ovarian adenocarcinoma that had recurred - she had just celebrated her 45th birthday. She had her tumor surgically removed and went into remission for about a year. Then it came back with a vengeance, spreading to her lymph nodes and ultimately taking her life. The chemotherapies, I believe, destroyed her immune system and prevented any chance of her developing an immunity to cancer antigens.
If we can increase and unleash more tumor infiltrating lymphocytes using an intratumoral electroporation of combination with anti-pd-1, anti-ctla-4, etc checkpoint inhibitors, then we will probably see much greater response rates with improved progression free survival and overall survival in metastatic solid tumors.
If my thought experiment proves to be correct, then Oncosec will be leading a revolution in cancer treatment. There is simply no way I can overstate the significance of achieving an electroporated version of checkpoint inhibitors.
