OncoSec Medical Inc (ONCSQ)

[hschlauch]

There is excitement around IDO inhibitors right now (e.g. see Incyte's epacadostat), especially when they are used in combination with other checkpoint inhibitors.

For example, see Questions Remain About Immunotherapy in Melanoma - http://www.curetoday.com/articles/questions-remain-about-immunotherapy-in-melanoma?p=1.

Here is a little bit of what Jason Luke has to say:

"We are very excited about the idea that combination strategies might double down on T-cell inflammation where it is present. Our research suggests that between about 50 percent to 70 percent of patients with advanced melanoma have active inflammation in their tumor microenvironment, which we think is the rationale for why PD-1 antibodies are so effective. Along that same sort of approach is the addition of other tumor microenvironment factors or inhibitors, such as the IDO pathway, which also looks quite exciting."

How do IDO inhibitors differ from other types of immunotherapies?

This again goes to the concept that some patients have an immune infiltrate in their tumor. When that is present, we see that the T cells drive an inflammatory phenotype in which the tumor cells react to the immune cells that are in the tumor microenvironment, upregulating certain molecules—one of them obviously being PD-L1, the important one for PD-1 antibodies."

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The observations that I have made with the ECHO 202 phase 1 trial testing epacadostat with pembrolizumab, suggests to me that an IDO inhibitor combination will ultimately be on par with combination T-vec plus pembrolizumab and yervoy plus opdivo. All of these combinations seem to hover around 58% ORR for metastatic melanoma in all-comer trials; it's actually quite interesting to see the consistent response rates.

Jason Luke's comments confirm my suspicion that tumor cells adapt to immune cell pd-1 phenotype upregulation during inflammation by upregulating their own pd-l1. And what pathway leads to significant inflammation? Yep, interferon gamma, a byproduct of IL-12.

Also, Jason's excitement over IDO inhibitors is something to keep in perspective when we try to extrapolate the upcoming phase II EP IL-12/pembro combination data. Like I have said before, technically speaking, the biomarker that is being used and developed by UCSF investigators is an exploratory biomarker. Despite it not being a validated biomarker, I think it is absolutely predictive of response/non-response in metastatic melanoma; it simply requires more validation from others. If we see responses in the upcoming data release for ONCS's/UCSF's EP IL-12/pembro phase II combination trial - presented as a late-breaking oral poster - it is my opinion that EP IL-12 is significantly driving pd-1/ctla-4-positive TIL phenotype, thus leading to the responses. From a statistical perspective, the likelihood of any responses occurring in the trial due solely to pembrolizumab is almost infinitesimal based on the "discovery" and "validation" cohort data.