GoodJohn, here is what I'm thinking...
To drive a significant abscopal effect and immune response to cancer tumor cells, you would need recognition of neoantigens. Systemically administered checkpoint inhibitors are ultimately delivered to locations all over the body. This route of administration not only leads to severe toxicities when used in combination with other checkpoint inhibitors, but the effect is non-localized. In theory, or at least in my mind, electroporating checkpoint inhibitors would drive more significant localized tumor regressions in a shorter amount of time than systemic injections. In addition, you would see far fewer severe adverse events versus combination checkpoint inhibitors administered systemically. Electroporating an anti-pd-1, anti-ctla-4, etc monoclonal antibody (checkpoint inhibitor) with IL-12/GP96/OX40L would drive a profound immune response and abscopal effect because greater numbers of neoantigens would initially become exposed in the context of an inflamed tumor microenvironment. Metastatic lesions would then be subject to TIL with tumor specific neoantigens. There would theoretically still be a need for systemic applications of checkpoint inhibitors in some metastatic situations, but the electroporation of the genes would substantially eliminate systemically delivered checkpoint inhibitor use.
Electroporating DNA for checkpoint inhibitors would 1) speed up neoantigen release and presentation to naive t-cells; 2) provide robust and continuous localized expression for perhaps up to a couple weeks; 3) lead to a profound abscopal effect and important innate immunity; and 4) provide a safer alternative to repetitive systemic checkpoint inhibitor use. Of course, the checkpoint inhibitors would work best in the context of an inflamed tumor microenvironment (IL-12) that contains antigen chaperones (GP96) and co-stimulatory agonists (FC-OX40L) that are capable of polyclonal expansion and that are responsible for memory precursor cell production. What this comes down to is complete tumor regression in treated lesions in a relatively short amount of time, and a robust innate immune response that is capable of driving TIL in metastatic lesions.
