Replies to post #824387 on NorthWest Biotherapeutics Inc (NWBO)

[Slave1]

Gary,

I am sorry about your friend. Stage 4 with bone involvement is a brutal diagnosis, and the fact that she has never complained tells you something about who she is. I hope the time she and her husband are making the most of is full and good.

Let me clear up a couple of things on the science, because I actually think it is less mysterious than you might expect, and understanding why it works may give you more confidence in what it could do, not less.

First, Ori does not make more potent dendritic cells. Ori's IRO is a suspension cell bioreactor. It handles CAR-T, TIL, NK cells. It cannot manufacture DCs at all because DCs are adherent cells that grow attached to surfaces. NWBO's EDEN bioreactor was purpose-built for that. So any potency improvement in the DC product comes from the DC science itself, not from Ori.

Second, your aspirin analogy is more connected to this science than you probably realize. You are right that people take aspirin without understanding why it works. But aspirin actually has different mechanisms depending on the dose. At the lowest dose, it preferentially inhibits thromboxane A2 through COX-1, which is the antiplatelet effect. At higher doses, it inhibits COX-2, which produces prostaglandin E2, PGE2. Here is the irony: PGE2 is the single molecule Kalinski designed his entire platform to eliminate. PGE2 is what drives M2 macrophage polarization in the tumor microenvironment. PGE2 is what expands regulatory T cells that suppress the immune response. PGE2 is what the standard DC maturation cocktails use, which is exactly why those standard DCs produce CCL22 and recruit Tregs instead of killers. The alphaDC1 cocktail was specifically designed without PGE2. And the CKM conditioning regimen includes celecoxib, a selective COX-2 inhibitor, specifically to block PGE2 production at the tumor site before the cellular products arrive. The epidemiological data showing aspirin reduces cancer risk, particularly colorectal cancer, likely works through this same COX-2/PGE2 axis. So your analogy landed closer to the science than you intended.

Now, the mechanism behind why the vaccine concentrates T cells at the tumor is understood, and it flows directly from removing PGE2. When alphaDC1 dendritic cells are activated, they produce specific chemokines, primarily CXCL10 and CCL5, that act as homing signals for cytotoxic T cells and Th1 cells. These chemokines bind to CXCR3 and CCR5 receptors on the T cells the DC just educated, creating a chemical gradient that pulls those T cells directly to the tumor site. At the same time, because PGE2 was eliminated from the maturation cocktail, the alphaDC1 does not produce CCL22, the chemokine that recruits regulatory T cells. Standard PGE2-matured DCs produce CCL22. The alphaDC1 does not. So the vaccine concentrates the right T cells at the tumor while not recruiting the wrong ones. That is what Kalinski engineered over 25 years, and PGE2 elimination is the thread that runs through all of it.

The poly-I:C you mentioned (Poly-ICLC is the stabilized clinical-grade form) is actually already part of the alphaDC1 maturation cocktail. It is also the basis of the CKM conditioning regimen, where a TLR3 ligand plus interferon-alpha is administered systemically to reprogram the tumor microenvironment before the cellular products arrive. In the neoadjuvant triple-negative breast cancer trial at Roswell Park, that regimen produced 78% favorable pathologic response associated with lack of recurrence. Triple-negative breast cancer. The most aggressive subtype. That data is published.

On your friend. I cannot speak to her specific situation from here. What I can tell you is that Linda Powers said at the December annual meeting that in 2026, NWBO plans to expand compassionate use to most types of solid tumor cancers, not just brain cancer, and plans to offer DCVax-Direct in addition to DCVax-L. She also confirmed that DCVax-Direct manufacturing is ready and the Phase 2 indication is a below-the-neck solid tumor. I do not know whether your friend's specific situation would qualify or when enrollment would open. But the path you are hoping for is one the company has publicly stated it is working toward.

Your friend is fortunate to have someone paying this much attention on her behalf.

Pulling for her.

[RRP60]

Gary, briefly touching your last paragraph, in real world, bones are frequently involved  in breast cancers as metastatic disease. When they respond to treatments, the body will try to regenerate bone minerals there to remodel those lesions. This bony remodeling will be seen as persistant bone lesions in imaging studies.  Many a times these lesions will stay back inspite of improvement in the soft tissue lesions and improvement in tumor markers. When we subject these patients to hybrid imaging , these turn out to be inactive lesions with healing blastic component in these bone lesions. Nothing need to be done. Well once we get approval for dcvax l and D along with activated dcells and checkpoint inhibitor combinations, so much can be done in terms of off label use at every hospital level for the smoldering disease or recurrence. We have already come a long way in tackling breast cancer , this is what i saw over the years. Its still a dreadful condition. But with the available treatment options and newer imaging techniques, patients are getting so much of hope. Once we get our treatments to the market, many of these patients will out live these cancers. Iam more than positive about this.