The current TAVO plasmid construct containing just IL-12, along with the unimproved electroporation device, have their limitations. That doesn’t mean that the current TAVO IL-12 plasmid construct and EP device won’t work for some patients; it just means that there are opportunities for improvement on the plasmid construct, the encoded genes and transfection efficiency. The Merkel Cell trial data show that IL-12 expression using the first gen EP device and plasmid construct is not always good, perhaps due to tumor tissue heterogeneity and/or voltage parameters. I think adequate IL-12 expression was observed in something like 75% of those patients. That begs the question regarding transfection efficiency in the melanoma trials. However, observing 20%-30% durable responses in refractory anti-pd-1 patients with advanced melanoma is superior to anything else currently reported in clinical trials including Dynavax’s SD101. The TAVO plus pembro combo has demonstrated great PFS, DOR and safety as well.
The intratumoral administration of encoded IL-12 is a rational approach when combined with electroporation. The electroporation procedure by itself contributes to tumor antigen release. This is extremely important for adaptive immunity. Expressed IL-12 that originates from the encoded plasmid activates NK cells, which then start producing IFNg, CCL5 (a chemokine that attracts dendritic cells), FLT3 ligand and other chemokines. The FLT3 ligand then expands the dendritic cell population, thus improving antigen presentation to CD4 and CD8 T cells. Unfortunately, Tregs with their CTLA-4 can control antigen presentation and priming by outcompeting CD80 and CD86 on dendritic cells. This is why adequate IL-12 expression is so important intratumorally. If transfection is poor, then you won’t see much improvement in NK cell activation and expansion, and antigen presentation/priming will be insignificant. To overcome this priming hurdle, I believe several things can be accomplished without dramatically modifying the company’s electroporation platform:
1. Make improvements to the EP device and voltage parameters - check.
2. Improve the plasmid construct to ensure greater transfection - check.
3. Encode FLT3 ligand with IL-12 to overwhelm CTLA-4 on Tregs with high densities of dendritic cells - unknown if this is being actively pursued in the next product although preclinical work demonstrates that they have thought of it; or
4. Encode anti-CTLA-4 with IL-12 to eliminate the immune suppressive effects caused by CTLA-4 - no evidence of Oncosec pursuing this approach.
5. Encode anti-PD-L1 with IL-12 and FLT3 ligand (or anti-CTLA-4) - intratumoral administration of anti-PD-L1 affimers has been mentioned, but it is unknown whether or not this is really in the cards.
