NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

We can do one of two things with information we don't like because it proves a belief of ours wrong--accept it or deny it. Not going to debate this out, just posting it and you all can do either. Up to you:

The method for manufacturing DCVax-L is well outlined in UCLA studies (where they licensed it from, and where those patents originate from) and the protocol itself. No dedicated maturation step or otherwise controlling measures are taken to ward off inhibitory cytokines (including IL-10). Maturation of DC is essential for their migration and that is essential to elicit t-cell or other immune responses:

PURPOSE:

We have investigated the capacity of immature and mature monocyte-derived DCs pulsed with melanoma-associated peptides (gp100 and tyrosinase) to induce a primary cytotoxic T-lymphocyte response in vivo.

EXPERIMENTAL DESIGN:

Advanced HLA-A2.1(+) melanoma patients were vaccinated with peptide- and keyhole limpet hemocyanin (KLH)-pulsed DCs, either immature (9 patients) or matured by monocyte-conditioned medium/tumor necrosis factor alpha/prostaglandin E(2) (10 patients).

RESULTS:

All patients vaccinated with mature DCs showed a pronounced proliferative T-cell and humoral response against KLH. By contrast, KLH responses were absent in most of the patients vaccinated with immature DCs. Delayed-type hypersensitivity (DTH) reactions against antigen-pulsed DCs were only observed in patients vaccinated with mature DCs and not in patients vaccinated with immature DCs. MHC-peptide tetramer staining of DTH-derived T cells revealed the presence of specific T cells recognizing the melanoma-associated peptides in 1 patient. In a second patient, DTH-derived T cells showed specific lysis of tumor cells expressing the antigens used for DC pulsing. Only patients vaccinated with mature DCs showed objective clinical responses. Interestingly, both patients with long-term progression-free survival (22 and >40 months) were both vaccinated with mature DCs and demonstrated antigen-specific T-cell reactivity of DTH-derived T cells.

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14613986

and

In 2003, a phase I/II clinical trial treating stage IV metastatic melanoma patients with autologous, antigen-loaded moDCs confirmed the superiority of mature DCs to induce strong immunity, as the immunological response against both included TAAs and the control antigen keyhole limpet hemocyanin (KLH) was improved in the majority of patients treated with mature DCs, as opposed to immature DCs (54). Strikingly, tumor regression could only be observed in patients of the mature DC arm, indicating that activating DCs prior injection improves clinical response as well. Other groups that employed modified maturation cocktails made the similar observations that DC maturation is necessary for the induction of a superior immune response (55–59)

http://journal.frontiersin.org/article/10.3389/fimmu.2014.00165/full

However, with whole tumor lysate (WTL) loaded DC using freeze-thaw necrosed lysate (like DCVax-L or AV0113), something negative regarding maturation occurs:

Tumor cells freeze-thawed in vitro to generate ostensibly necrotic and hence, potentially immunogenic lysates, inhibit full DC phenotypic maturation and inflammatory cytokine release. These effects are broad, extending over a range of tumor models, mouse strains, and maturation stimuli. These data also show that DCs pulsed with freeze-thaw lysates are likely to skew CD4 responses away from an optimal TH1 profile, are unable to cross-present lysate-derived TAA, and are less effective at activating specific CD8 cells even when favorably loaded exogenously with specific peptide epitopes.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901408/

Pre-stressing lysates before freeze-thaw cycling can help, but of course NWBO doesn't do this with their old tech:

Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

(same link)


Another study tested various whole tumor cell preparations and found that freeze-thaw necrosed lysate loading was ineffectual when compared with other loading methods:

We demonstrated that mice treated with bone marrow-derived DCs pulsed with HOCl-oxidized whole tumor cell lysate of ID8 expressing ovalbumin (ID8-ova) had the best tumor control with >60% cure rate [41]. In contrast, mice that were treated with DCs pulsed with freeze-thawed (100%) and UVB-irradiated ID8-ova whole tumor cell lysate (70%), succumbed to tumor growth and ascites formation. The superiority of HOCl-oxidized whole tumor cell lysate preparation could be attributed to the induction of less Treg cells in peripheral blood and absence of serum IL-10 in the vaccinated mice and not in mice treated with other UVB-irradiated or freeze-thawed whole tumor lysate preparations. We translated these findings into a phase I trial by immunizing patients with autologous DCs loaded with autologous whole tumor cell lysate prepared with HOCl-oxidation [41].

So immature, or not fully mature DC have trouble migrating, and induce basically no effect. We are talking of course about intradermally injected DC vaccine,a nd for the moment not intratumorally injected vacc (like DCVax-Direct).

That is a problem with DCVax-L. But that might be less of an issue if you can show that something like 80% of DC migrate when they are mature. Then if say 10-20% of the DC in DCVax-L are mature (which I don't see how but ya know, let's just say they manage that with all those inhibitory cytokines) then maybe 16% or so of the DC could theoretically migrate with DCVax. But actually, and unbelievably, many trafficking studies on mature DC injected intradermally have shown only about 1% on average migrate. And at most they found 4% migrated in one subject:

The mean overall redistribution of injected cells from the ID injection depot to draining lymph nodes was relatively constant, with a median migration of 1.0% (range 0.2-4.0%, Figure 1B)

http://clincancerres.aacrjournals.org/content/early/2011/07/19/1078-0432.CCR-11-1261.full.pdf

Wow, right? What happens to the other 99% of them?:

Since intravenously (i.v.) injected, ex vivo generated DCs fail to induce potent skin-homing T cells in mice and appeared to be less efficient in inducing TH1 responses in humans, previous clinical trials focused on subcutaneous or intradermal (i.d.) administration of the vaccines (60–62). However, using 111In-labeling and scintigraphy, we could show that most of the injected DCs remain at the injection site, where they rapidly die to be phagocytosed by macrophages (42, 63, 64). Pretreatment of the skin with cytokines, toll-like receptor (TLR) ligands, or activated DCs did not lead to increased migration (64)

http://journal.frontiersin.org/article/10.3389/fimmu.2014.00165/full

Administration of various cytokines, mature unloaded DC or TLR agonists (as UCLA continue to try) was useless in producing a measurable increase in migratory DC. The only thing that helped was lowering the concentration of DC per shot. And yes, DCVax-L does this, but before you get too excited it only increased migration to 1.5% (2.5 mil DC).

See figure 4:

http://clincancerres.aacrjournals.org/content/19/6/1525.long

This was succinctly stated in the following text:

One of the major problems still associated with dendritic cell vaccination pertains to dendritic cell traffic. Therapeutically injected dendritic cells need to reach the lymphoid organs in numbers large enough to elicit robust immune responses. Typically, this dendritic cell journey will be from the cutaneous injection site to the draining lymph nodes. Only small percentages of the injected dendritic cells make it to their final destination, as has been shown in mouse models [173] and also in human volunteers by means of radioactively marked cells [173-176]. This is probably an important reason why no strong anti-tumor responses have yet been obtained.

from: Leukocyte Trafficking: Molecular Mechanisms, Therapeutic Targets, and Methods

So if only about 1% migrate when the whole of them are adequately matured, how many of them will migrate when they are most or all immature (as is almost certainly the case with DC in DCVax-L)?

0%, that's how many.

They are all phagocitized by macrophages. The entire DCVax-L medium-blueberry sized shot is quickly engulfed and destroyed. The patient gets some inflammation at the injection site and sometimes transient fevers (as with basically any biologic invasion). Really no other AEs. Sounds familiar, right?

Why did Woodford invest? Well at some point DD stops. Imo his team's DD was just lacking. That's all. Prob taken in a bit by the MHRA's adoption of DCVax-L and the HE program as validating the tech in some way. But the only thing that validates a therapy is controlled data. Both programs picked up DCVax-L because patients have no other options and those were meant to help small biotechs get their potentially efficacious therapies to market. That's all, nothing else about it tells you anything in terms of efficacy.

Lots of billionaires have made bad bets. Why does he have 2.5x the holding of NWBO in another small cap bio? He likes it better, yeah? Why do you disagree with him?

So I did not change my stance on why I think it will not work, these things all play into each other.

GL out there! Maybe sell and just move the funds into WPCT if you are a believer in him and his team's DD and their investment choices including allocation of AUM. Choosing a different path means you think you can do it better than him, no?