Some random thoughts...
If I'm not mistaken, the positive predictive value for >30% PD-1/CTLA-4-positive TIL was also 100%. Relative frequencies that approach 20% from the higher end demonstrate significantly less predictability. ONCS is specifically selecting patients with a <25% PD-1/CTLA-4-positive TIL profile.
I tend to think that EP IL-12 is augmenting these exhausted TIL phenotypes, thus leading to responses in otherwise non-responders treated with monotherapy checkpoint inhibitors.
It looks like combination checkpoint inhibitors, e.g. Opdivo and Yervoy, are able to achieve significantly more responses in metastatic melanoma than either treatment used alone. I find this to be intriguing, because there must be patients with lower relative PD-1/CTLA-4-positive exhausted cells who are responding to dual checkpoint inhibitor combination therapy. Perhaps the combination of checkpoint inhibitors is simply allowing existing TIL to mount a stronger attack due to the release of more brakes. In other words, they aren't necessarily increasing the number of TIL, they are simply allowing more existing TIL to mount an attack. For example, despite the relatively lower frequencies of CTLA-4 positive TIL in most tumors, the inhibition of the checkpoint might drive just enough CTLA-4-expressing TIL to control disease progression, thus leading to a response. Alternatively, the addition of Yervoy to supplement Opdivo might also be leading to a reduction in the number of Tregs rather than just significantly altering the number of TIL available to mount an attack on tumor cells.
I continue to believe that the gold standard for metastatic melanoma and potentially other solid tumors will eventually include combinations of mAbs (e.g. anti-PD-1 and anti-CTLA-4), immunoregulatory cytokine (e.g. EP IL-12), and antigen-specific T cell activators (e.g. Gp-96lg/OX40L).
I also think EP IL-12 is going to be integral to a lot of solid tumor combination treatments due to its ability to induce interferon gamma production, and consequently, differentiation of naive cells into Th1 activated cells. Th1 cells also produce interferon gamma, thus contributing to a positive feedback loop that allows for expanded T cell activation. Interferon gamma induction also leads to increased macrophage production, which stimulates antigen processing.
Moreover, if you combine an antigen chaperone like Heat Biologics' Gp-96lg and you allow it to be electroporated in the tumor microenvironment, you would theoretically have 1) chaperones that carry tumor-specific neoantigens to 2) a significant population of antigen presenting cells, which 3) were expanded by IL-12 and prior T-cell activation through interferon gamma production, 4) compounded differentiation of naive T-cells to antigen specific Th1 cells, leading to 5) a robust expansion of exhausted TIL. Those exhausted TIL will generate higher frequencies of PD-1 and CTLA-4 expression, thus establishing the requisite phenotypes for anti-PD-1 and anti-CTLA-4 combination therapies.
