That guy hasn't gone anywhere. I'm being cautious given the slightly different patient population (i.e. all anti-pd-1 non-responders) we're dealing with in the PISCES trial. I wasn't exactly impressed with the responses in the OMS-I102 Trial for actual anti-pd-1 nonresponders; however, patient selection was based on exhausted CD8 T cell levels and those patients who progressed had little to no detectable levels of these TILs. I don't think the PISCES trial will have so many patients with such low levels of CD8 T cells at baseline, but you just never know.
With that said, I am still very impressed with the PFS and DOR data as well as the depth of response (nearly every patient who responded eventually experienced a complete response). That is quite impressive.
I've been re-reviewing the available data from Oncosec's trials to better understand why some patients are responding to EP pIL-12 in combination with anti-pd-1 agents and others are not. I'm beginning to think that innate immunity (i.e. activation of NK cells) is the most critical immediate effect with EP pIL-12. These NK cells, once activated, "communicate" (through FLT3L) with dendritic cells. If these NK cells aren't already present or are insufficiently activated by IL-12, you probably won't observe an expansion in the number of antigen presenting cells, e.g. dendritic cells, due to insufficient FLT3L expression. Without adequate antigen presentation, CTLA-4 on Tregs can control downstream CTL activation (CD8 T cells, for example). Obviously, the ultimate goal is to generate sufficient numbers of tumor antigen-specific CTL in the tumor microenvironment, but the path to get there requires sufficient antigen presentation. If IL-12 can't do it alone in some patients, then the next best thing would be to bypass NK cell activation and directly produce FLT3L intratumorally or in tumor draining lymph nodes to expand the population of dendritic cells where they are needed most. In my opinion, this would diminish or eliminate local immune suppression caused by CTLA-4 on Tregs.
I believe ONCS is heading down that road - encoding both FLT3L and IL-12 on a single plasmid - with their first multigene product. Unfortunately, that still hasn't been clarified by the company.
