Replies to post #42183 on OncoSec Medical Inc (ONCSQ)

[hschlauch]

I would think first line therapy is very much in the cards for stage III/IV melanoma. It would be most prudent for them to identity an optimal biomarker threshold in the first-line setting as you're alluding to, so that patients who might respond with anti-PD-1 monotherapy don't receive more treatment regimens than they need.

I certainly think EP pIL-12 with pembro would work in other solid cancers, but they would have to use the new GENESIS EP device if they're directly treating subcutaneous and visceral lesions. The first new PIIM construct is very likely going to be much better than Immunopulse IL-12 due to the fact that the genes are p2a linked and the PIIM includes encoded genes that will vastly improve antigen presentation and T cell activation while mitigating Treg effects intratumorally.

I will read up on HALO at some point and provide some feedback.

[seventhwave]

hslauch, I second ITT's call to do a comp with HALO's approach - here's a note of relevance...

Key Opinion Leader Manuel Hidalgo, MD, PhD Harvard Medical School and Beth Israel Deaconess Medical Center-"Pegylated hyaluronidase, may, at the end of the day, make the tumor hot for immunotherapy."

http://bit.ly/2ndzUyB

[hschlauch]

ITT, getting back to your question about Halo's PEGPH20...

I think hyaluronan's role in the progression of pancreatic, breast, colorectal cancer, etc is misunderstood by Halozyme and clinical researchers. I don't think it is creating the physical barrier at all to immunotherapies or chemotherapies. In fact, it probably facilitates cell motility. Hyaluronan likely facilitates motility through binding with CD44 and RHAMM, both of which are overexpressed on pancreatic, breast and other cancers' cells. Having more hyaluronan available intratumorally means that when it binds with certain variants of CD44 and RHAMM on cancer cells, it will help to spread the cancer cells. This is where PEGPH20 comes in - the enzyme breaks down hyaluronan, thus mitigating the risk of metastases. I don't think PEGPH20 is driving immunity or turning cold tumors "hot" at all, it is simply reducing the spread of cancer cells. That isn't a bad problem to have necessarily, but there is going to be collateral damage with the PEGPH20 enzyme and it won't really improve antigen presentation, T cell activation, nor CTL proliferation.

What collateral damage? Hyaluronan also binds with CD44 on activated T cells, thus improving motility of those cells into the tumor microenvironment. Improving motility contributes to an increase in the number of tumor infiltrating lymphocytes and allows for systemic immune responses and an abscopal effect. By introducing PEGPH20 systemically, they are likely abrogating immune responses and contributing little to nothing when an anti-PD-1 agent is used. For advanced diseases, the addition of PEGPH20 won't add much value to combination therapies in my opinion.

And here is another big problem: systemic administration of the enzyme affects hyaluronan all over the body. The presence of it in skeletal muscle, bones, connective tissue, etc suggests to me that PEGPH20 will lead to very significant SAEs. You can already see this in the data when it is combined with chemo drugs. These patients experience severe pain, peripheral edema, along with several other serious side effects. The peripheral edema tells me that the fluid that accumulates with hyaluronan is being released when the enzyme breaks up the hyaluronan. The hyaluronan is found in these places for a good reason. It seems insane to me to have patients subjected to systemic administration of the enzyme.

ONCS's first PIIM construct encodes proteins that will be expressed intratumorally and in the presence of all available neoantigens. This will very likely lead to strong immune responses, an abscopal effect, and memory T cell production. It increases the number of CTLs, and due to their activation they start expressing a partially exhausted phenotype. This partially exhausted state is then ameliorated with an anti-PD-1. But without those CTLs, there is no point in using an anti-PD-1 agent. You absolutely need a significant number of tumor-antigen specific CTLs to drive robust and lasting responses, i.e. tumor cell destruction. PEGPH20 probably won't accomplish any of that, but it will perhaps slow down the formation of metastases in some early stages of cancer.