kabunushi,
If you understood how Direct as tested in Phase one had its impact hogtied you would not be wondering about its future impact especially now with hyper activation and the Roswell Park tech added in which will create a much more complete immune response. The science dictates this not some pie in the sky guess like so many studies start out with.
First, unlike L, Direct modifies the tumor microenvironment with on site activated and properly matured DC signaling which L does not do or create initially from innate en vivo DC populations picking up inflammatory signaling from T-cell attacks. What this means is that immune reaction that tries to shut down the active ongoing immune response to cancer ie checkpoints PD-1, PDL-1 are held off by DC Direct signaling that keeps the attack going if given the chance which did not happen in the Phase 1 study. What happens in the tumor microenvironment against Direct is that DCs are driven out by about two weeks due to the hypoxia encountered there. There are some things that can be done to counter this and give DCs another week or so but as tested, spacing of treatments longer than about 2 weeks allows the checkpoints in as the Direct DCs exit. This is why I made the call about the need for changing the interval between injections from longer than this to no longer than 2 weeks, at least initially, before NWBO even announced the change themselves.
Secondly, let’s go over what happened in the Phase 1. There were two different maturation states for DCs utilized, method A and method B with method A reported to be acting as a comparator (placebo like) to some extent for method B. There were also three different dosages utilized which were 2, 6, or 15 million cells per unit. This was done as testing for sufficiency for effectiveness and levels at which crowding at the injection site would interfere with same. The 6 million dose/unit was found to be the best performer of these 3. As already mentioned, spacing of treatments was suboptimal and led to immune response suppression in many to most patients. Add to this that only one tumor was injected when there were a majority of patients with multiple tumors (average about 3) and that treatment was stopped when treatment induced pseudoprogression was read as progression. This was also set up as a first in man designated trial for safety and created a recipe for what looks like failure to some. The complete opposite is true and those that know this outside of NWBO realize what is at stake and are doing everything they can to prevent this from moving forward outside of their control. They can control a $5-$20 share price pretty easily with an offer to purchase. If it runs past that there will be more trouble getting what they want.
Thirdly and last, the process for manufacturing Direct is already fully enclosed, cheaper to produce and the long path that L took now allows for a fully digitized Direct manufacturing process to pass product release regulations quickly instead of being stuck waiting on regulatory and process changes like L was up against. What this all means is that an improved Direct with hyper activated DCs and the Roswell Park tech added in will be easily approved and ready for scale up in pretty much all solid tumor cancer indications if the biomarker target from the Roswell Park tech is incorporated into the next trial and this will also create the kind of fast clinically acceptable response rates that the Phase 1 trial did not demonstrate because the MO was increased necrosis which happened after TIL infiltration that caused tumors to swell instead of shrink. A more complete immune response from product improvements (Roswell Park tech) and protocol improvements from optimized spacing, quantity, method, number of tumors injected, continuation of treatment after treatment induced pseudoprogression and patient screening based on ability to get donated monocytes turned into optimized IL-12 and TNF alpha producers amongst other cytokines which will all help create tumor shrinkage after pseudoprogression and an early stop to the trial or placed in a situation where it can be viewed as likely to do well and receive conditional approval while waiting out remaining data over the longer term which is what the recent proposal seen in this board today is all about.
The science has said for a long time “NOT IF BUT WHEN!” Dr Linda Liau pointed out recently that she knows what it’s like to swim with the sharks and they are the ones blocking the WHEN. The only thing I hope Linda Powers gives at least some of them that Dr Linda Liau is talking about is some chum before they get turned into shark steaks; ). Best wishes.
AI
