The ISR is pretty favorable for claim 1.
I have looked at the expression data for this first construct and genetic sequence and it looks like a significant improvement in IL-12 expression over the current IRES plasmid used in TAVO trials. In addition, the first claim includes encoded flt3l, which I strongly believe will expand mature dendritic cell populations intratumorally and improve signal 2 (co-stimulation) by increasing CD80 and CD86 on APCs, thus helping to overcome CTLA-4 on Tregs.
This PIM sequence also includes a common cancer antigen, NY-ESO-1. While the antigen by itself will facilitate vaccination against the antigen found in cancer cells, I think it will accomplish a couple additional things. First, because it is expressed with flt3l, it will help dendritic cells reach maturation, expand, and improve T cell activation intratumorally. This activation of CD4 and CD8 T cells, receiving the third signal through local IL-12 production, will contribute to increased interferon gamma. Once you improve interferon gamma levels intratumorally, usually you observe improvements in MHC I and II expression. This ultimately facilitates recognition of the cancer cells.
Second, the addition of the NY-ESO-1 to the plasmid construct helps with monitoring the immune response.
In other words, this PIM product helps to achieve signals 1-3 for T cell activation, and should improve MHC I and II expression intratumorally.
There are no products or platforms currently being tested, at least to my knowledge, that achieve all of these things. This would be a protracted intratumoral effect. Moreover, the electroporation procedure will inevitably release additional neoantigens intratumorally, thus serving as a highly personalized in situ vaccine strategy.
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