Thus far, ONCS nor any other company to my knowledge, has electroporated checkpoint inhibitor (specifically anti-PD1, anti-PDL1, anti-CTLA4, etc) DNA in tumor cells. In a previous post, I mentioned how Inovio is electroporating monoclonal antibody DNA, but they aren't anti-cancer checkpoint inhibitors. I'm curious whether or not a patient's adaptive immune response would improve if one were to electroporate checkpoint inhibitor DNA in non-metastatic solid tumors IN THE CONTEXT OF ELECTROPORATED IL-12, GP96 AND FC-OX40L (I originally left this contextual part out). Would the local administration (within the tumor microenvironment) of EP checkpoint inhibitors improve adaptive immune responses by allowing for a quicker and durable release of tumor-specific antigens (neoantigens) in the context of 1) an inflammed tumor microenvironment (IL-12), 2) antigen chaperones (GP96), and 3) co-stimulatory molecules (OX40L)? All of these agents administered together would theoretically drive a robust immune response that is capable of preventing recurrences, increasing responses, and greatly expanding progression free survival and overall survival.
We all know ONCS has been working with the GP96 and OX40L DNA plasmids in the preclinical setting. I think these agents administered together with IL-12 would greatly improve responses. But I also wonder if EP checkpoint inhibitors would add the "icing on the cake" if they too were to be administered in solid tumors in combination with these other agents.
As for metastatic lesions, I think the EP combination of IL-12/GP96/OX40L/anti-pd-1 (or anti-pdl1) would theoretically drive a significant abscopal effect by increasing the number of tumor infiltrating lymphocytes in non-treated lesions. In such cases where the TIL are "braked" by checkpoints in these distant lesions - which by the way is very likely due to the potential for exhausted phenotype in immune cells - at that point you would administer systemic checkpoint inhibitors. Again, this systemic application would be limited to advanced metastatic lesion situations - the TIL would be there, but they would be stopped by the checkpoints.
I additionally think there could be another use for an IL-12/GP96/OX40L/anti-pd-1 (or anti-pdl1) EP combination in the adjuvant setting, i.e. prior to surgical removal. This would theoretically contribute to an adaptive immune response that prevents recurrences or progression.
My primary question is whether or not the immune response would play out this way when you electroporate checkpoint inhibitor DNA in the tumor cells and in these settings.
Any thoughts?
