Replies to post #44902 on OncoSec Medical Inc (ONCSQ)

[chickpea598]

Couldn't agree with you more hschlauch. Complete disruption when the multi-gene construct gets under way next year. This year melanoma and PISCES data are just the tip of the iceberg. The market is completely underestimating what is happening at Oncosec Medical. I for one am very happy to remain a long-term shareholder.

[Hargrove]

On 12/27/17 "hschlauch" posted the following:

" I really do believe this first multi gene construct is going to be disruptive. The single issue I have with Immunopulse IL-12 is that it doesn't address overcoming the initial stages of immune suppression. That is, having too many Tregs at the start of an immune response isn't a good thing. Obviously, this isn't a problem for perhaps the majority of patients as we have seen remarkable complete responses so far. However, for those patients who haven't responded to the combination of Immunopulse IL-12 and Keytruda, it seems to be clear that they aren't activating enough CTL. I attribute this to too many intratumoral Tregs expressing CTLA-4.

I think this first PIIM construct will allow for APCs, like dendritic cells, to numerically overwhelm Tregs and their associated CTLA-4-derived suppressor effects. In theory, you may not actually need an anti-CTLA-4 agent. This new multi gene construct should lead to improvements in CD8 T cell activation and proliferation. I am actually so optimistic that I think it will convert nearly all anti-PD-1 nonresponders into responders, not just in metastatic melanoma but also in many other solid tumor cancers."

"hschlauch", thanks for just giving us the latest on the implications for ONCS' future regarding their first
PIIM Construct.......we don't have to look to far over the horizon to see a "BIG" success story unfolding for ONCS! We heard it here first!

THANKS!

[chickpea598]

hschlauch, your thoughts on this published article when you have a chance as it relates to Oncosec. Thanks! https://www.ucsf.edu/news/2018/06/410911/immune-profile-successful-cancer-immunotherapy-discovered?utm_source=ucsf_tw&utm_medium=tw&utm_campaign=2018_cancer_immunotherapy_prediction&utm_term=

[dangerM]

Wow, yes!

I saw this article mentioned in my twitter feed, but took your post as a reason to eventually improve my understanding of dendritic cells. It really took a bit of reading.

So cDC1 (or termed SDC here when in the tumor micro-environment) appear to be a rare but powerful sub-population of dendritic cells. They are the ones responsible for carrying long-peptide antigens (as presented to their MHC-II) back to the lymph node ("Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. ... Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade" https://www.ncbi.nlm.nih.gov/pubmed/27096321).

Interestingly, cDC1 only seem to need a little GM-CSF and actually prefer if there's more FLT3L, they really flourish then ("By use of the GMP adoptive system with a competitive transfer, we found a selective inability of Csf2rb-/- cells to reconstitute DCs at the tumor, here defined as the sum of DC1/DC2 using CD24+ CD11c+ gating. We found no effect on TAM1 and TAM2 repopulation, suggesting a unique requirement of CSF2 (GM-CSF) for tumoral DC development (Figure 4E) ... As DCs are prototypically driven by GM-CSF or FLT3-ligand (FLT3L), we assessed cytokine sufficiency to drive DC populations at the tumor using B16 melanoma tumor models engineered to express GMCSF or FLT3L. While GMCSF expression by the tumor drastically skewed the proportion of CD11b+ DC1, FLT3L expressing tumors drove unique expansion of the rare CD103+ DC2 at the tumor (Figure 4F)." - please note that to my understanding this article uses the name DC2 for CD103+CD11b"low" i.e. cDC1 or SDC, whereas cDC2 are called DC1 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254577/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254577/figure/F4/)

At last there's https://www.ncbi.nlm.nih.gov/pubmed/29429633 (quote as reference #15 in the most current article by Barry). This article already described the "NK-cDC1-axis" and characterizes NK as attractors for cDC1 (via CLL5 and XCL1), but had not identified them as producers of FLT3L as Barry recently did ("We found that in vivo blockade of CCL5 and XCL1 resulted in markedly reduced cDC1 accumulation within tumors ... In NK cell-depleted mice, Ptgs1/Ptgs2 BRAFV600E tumors expressing XCL1 grew more slowly than mock-transduced cells, suggesting that XCL1-mediated recruitment of cDC1 can partially compensate for the loss of tumor immune control caused by NK cell ablation").

I am still suffering a bit from information overload, but I am very, very impressed.

The only thing one could ask for would be CLL5 or XCL1 added to the cocktail, in case there are too few or no cDC1 in the tumor waiting for maturation/expansion by FLT3L. However, these additions would not always help, since tumor produced prostaglandin E2 seems to (both harm NK cells) as well as diminishes cDC1's attraction to CLL5/XCL1*.

If any reader feels somewhat run over here - I do, too ;-)



*
"[secretion of CCL5 and XCL1] was strongly reduced in a dose-dependent manner in presence of PGE2 (Figures 4E and 4F). Survival of NK cells was also markedly reduced by PGE2 even in the presence of IL-2 (Figure 4G).

...

Therefore, chemokine expression alone is not sufficient to recruit cDC1 into PGE2-producing tumors, suggesting that PGE2 not only suppresses CCL5 and XCL1 production by NK cells but also impairs cDC1 responsiveness to the chemokines. Consistent with that notion, cDC1 exposed to conditioned medium (CM) from PGE2-producing tumors were impaired in their migration toward CCL5 and XCL1 (Figures S5E and S5F).

These data indicate that PGE2 can block the ability of cDC1 to migrate toward the chemokines CCL5
and XCL1 in part by inducing downregulation of the respective receptors."