Replies to post #33772 on NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

You do know EVERY small cancer company drops a hint about partnering with every successful cancer company out there right? -IC

Flipper mentioned ORR with DC vaccines, but these have been in operable cases with residual tumor, and with the vacc as an adjuvant or immediate follow up to chemo (and so ORR possibly confounded). In fact, criteria in the Direct trial also demands some pretreatment "to reduce tumor burden."

No DC vacc, to my knowledge, has shown ORR in inoperable cases, unless injected intratumorally. And that has only occurred in less advanced patients or in small skin lesions etc but not in large, robust intraorganal tumors. Late stage, advanced patients with large lesions and multiple mets are obviously a very difficult demographic to treat (and prob out of reach for DC vaccines alone), but unless you can show some effect here with an acceptable degree of safety you cannot use the exp tx to treat less advanced patients. These stage IV or even lesser stage inoperable patients have nothing to lose, and that is why FDA allows a tx never before used in vivo to be tested on them.

I think it's pretty clear why LP started mentioning checkpoint inhibitors (CI) early this year. Direct data were mature enough to tell lots of things, including the inciting of t-cells but very little apoptosis. There is certainly activity though, and the normalization of the CD4:CD8 in one patient (I know just one, but..) is also encouraging. Increased circulating cytokines as well, but that was no real surprise. However, once again we see that t-cells are incited by the DCs but are rendered impotent via the immunosuppresive microenvironment of the tumor. And yes I think they overstepped their bounds in claiming as much in the SITC poster. To truly overcome that we would need to to see the ability of CD8+ cells to overcome various pathways, and that isn't evidenced by their mere appearance in tissue samples, though it's a great start.

Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8(+) T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8(+) T cells. The PD-1/PD-L pathway can be a good target for restoring antitumor immunity.

Back to why LP out of the blue brought up CI. If you are causing cytokine storms and some tumor necrosis, and stirring up t-cell activity (and possibly proliferation), you've got a very good pre-checkpoint inhibitor candidate. Preclin studies have already shown a DC vaccine combined with CI is more effective than either alone. And it seems Direct alone just can't get ORR. So, what's the logical next step to explore?

DC vaccines have always been shown more effective as adjuvants, that's why in the L trial temozolomide is continued throughout the booster schedule. Studies show increased survival with that methodology vs DC vacc alone.

CI do have some negative side effects, but their safety profile is much better than most chemos. This is a major advance in the treatment of cancer. And Direct probably can't compete. And if you can't beat em, ...

I like the idea. I have for a while. And for these inoperable cancers (which is where CI are being tested), Direct makes perfect sense. But it's tricky, incorporating the two schedules. It's possible DCVax-Prostate, which is pre-loaded with a synthetic antigen, could advance in adjuvant CI trials right away (notice Provenege + CI has a trial ongoing?), but apart from that you need significant tumor tissue to load the DCs. I suppose a bunch of needle biopsies could get you 3 gm, but you'd need a LOT of them. That's maybe too fanciful. Probably just a minor surgery on an accessible lesion would do. Otherwise, you need Direct. And I think that may be a better fit anyway.

CI + Direct, or CI + DCVax-Prostate.

Okay cool. But when?? Here's the part where we stop trying to be scientists and realize we are retail investors. This is about money, and time = money. And timing is an essential part of the profitability equation. Timing of entry in a security in particular for investors.

So $660mm market cap, not fully diluted. One Ph III candidate for a very small pop of patients around the world, entering into a market with a vacc that is tricky to manufacture and a market difficult to qualify (and the only precedent a Chap 11 flop). It's not sufficient enough to figure incidence * projected tx cost - COGS. That formula is far too simplistic.

Just not enough data. Everything is hypothesis right now. Worth a bet? Sure. But I don't think over $7 as a cost basis. Woody's is $6.60 btw. At this point I think that's even too high.