NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Anybody wonder what a DC Train is? Please, consider the following:

"Finally, histologic analyses on the tissue samples, taken over and around the injection site, were analyzed (Fig. 4C). Extensive hypoxia was observed at the injection site [CAIX stain (brown); top ]. Furthermore, at the lower cell numbers, we observed trains of migratory cells (bottom). These trains appear to be migrating along the muscle tissue and were completely absent with samples with 15 and 10 × 106 million DCs." -- clincancerres.aacrjournals.org/content/19/6/1525.long

Still, why was there FDA/NWBO confidence in returning to a monotherapy + SOC phase III trial for a potentially pivotal determination regarding DCVax-L efficacy. One thing that researchers learned is that there is another way, besides adding a TLR-7 agonist to protect dendritic cells at the injection site and during their migration. While larger dose amounts of DCVax-L are generally a good thing, the key is to reduce dose per actual injection. In other words, optimally, if you extrapolate the idea, you'd want several injections 1cm apart adding up to one larger dose. The reason behind this is that scientists found that too many dendritic cells in one injection site causes "crowding." This causes lack of oxygen, or hypoxia around the recently injected DCs, and if that does not kill them outright, immune cells within the body, macrophages eliminate other sluggish dendritic cells before they can migrate.

Solution? By injecting a smaller dose, and I have to admit I think this is really cool, the dendritic cells quickly gather into what scientists refer to as "trains" of DCs. These trains then migrate from the injection "station" as it were, to the lymph node to express the tumor antigens and costimulatory molecules to the t-cells. See what just happened? A TLR-7 agonist was no longer needed to protect DCs from being killed at the injection site, nor was it needed to achieve formation and migration to the lymph nodes. Before I go on, I must add a reality check. Researchers must also ration dendritic cells, because they make it from whatever amount of limited PBMC and tumor lysate (for pulsing the DC) there is, the choice in the phase III trial was to only use two nearly simultaneous injections per administration at 1.25x10^6 dendritic cells. That's the best dose per injection, but ideally it would be nice to have even more injections per administration. Still, it is clearly better than one injection and likely/theoretically double the number of dendritic cells that migrate and ultimately evoke an immune response.

So simply by changing/lowering the amount of DCs in each injection, that particular benefit from the TLR-7 agonist is likely no longer necessary. But what about the TLR-7 agonist's ability to charge inflammatory t-cells that then create more inflammatory responses within the GBM tumor? First, it must be pointed out that it is not yet known whether it was the added inflammatory response induced by the TLR-& agonist that increased efficacy further in the earlier DCVax-L trials. As discussed above, UCLA is conducting a parallel phase II trial to make this determination. Regardless, one of the primary questions the phase III trial will resolve is whether statistically significant efficacy results can be achieved in a blinded trial using DCVax-L as a monotherapy (when added to standard of care). -- flip