On a related topic (development of DCVax-Direct): It was extremely encouraging news that the DCVax-Direct technology transfer from Charles River Labs’ Cognate subsidiary to Advent had already begun nine or ten months ago. This was the first critical step to restarting that program, which will almost certainly involve basket trials as a monotherapy for multiple solid tumor cancers (recall that the phase I trial had over a dozen different cancers including; breast, lung, ovarian, colorectal, bladder, pancreatic, melanoma, sarcoma, and others). As a reminder, this is what Linda and Les said about DCVax-Direct at the shareholder meeting:
Les: “And the way that Advent is finishing up ,even right now, things like the restart of DCVax-Direct, which will be coming up, and has done, put a lot of work on that in the last 7, 8 months.”
Linda: DCVax-Direct . . . very near and dear to our hearts. We have been eager to restart this program for a long time. And we, the first thing, of course, that we need to do, is restart the manufacturing. As it turns out . . . and this will be something that we'll make a public announcement when the time is right . . . anytime that you do a technology transfer process, because that product was only ever produced in the US, by parties who are no longer there, and so we had to do a technology transfer process to the Sawston facility.
Whenever you do a technology transfer process, you have to draft a whole new set of SOPs, (standard operating procedures), regulatory documents, all of that. And usually a technology transfer, especially for a cell therapy, is a minimum of at least 6 months of work. And then we've had two additional, challenges, which I think, we're on our way to having behind us. One that related to the machine that we use for the first stage of the process, and one which related to some key ingredients in the process. And when we come to that announcement, we'll we'll sort of explain all that.
But suffice it to say, restarting the manufacturing process, is a significant priority for us, in this going forward period, and you'll be hearing from us about that. And then once we've got the manufacturing restarted okay. Then we come to the last grouping of priorities. Once we have the manufacturing restarted, we are very eager to get the clinical trials underway to proceed. I guess, I don't know to what extent people remember, but the early stage trial that we did, was a phase 1 trial which, in which, it was conducted at MD Anderson.
We treated 13 different types of solid tumors, very diverse, pancreatic, breast, sarcoma, lung, colorectal. I mean, very diverse solid tumors, with very encouraging survival extensions in patients who were metastatic, and had failed every other treatment, and were pretty, pretty broken. DCVax-Direct. So that was really encouraging in the phase 1 trial. And even today, with all the billions that have been spent by the whole pharma and biotech industry on cancer treatments, when you have metastatic solid tumors today, there's not very much for you, as a patient.
And DCVax-Direct is a wonderful technology because it's directly injected into the tumor. The tumor that can't be surgically removed, either because there's too many of the tumors, or because it's located somewhere, where you might bleed out on the operating table, whatever, that are inoperable. But you, with image guidance, any form of image guidance, physician's choice, you can reach pretty much any location in the patient's body, to inject directly into the tumor. And even now, all these years later, we haven't seen, I'm not aware . . . maybe it's out there, but I'm not aware, we aren't aware . . . of any treatment like it, that's had the kind of encouraging results that the phase 1 trial did, and MD Anderson, in these patients. So we are very eager to get, get going again with that program. So that is, another priority.
This part was particularly interesting to me:
“Whenever you do a technology transfer process, you have to draft a whole new set of SOPs, (standard operating procedures), regulatory documents, all of that. And usually a technology transfer, especially for a cell therapy, is a minimum of at least 6 months of work. And then we've had two additional, challenges, which I think, we're on our way to having behind us. One that related to the machine that we use for the first stage of the process, and one which related to some key ingredients in the process. And when we come to that announcement, we'll we'll sort of explain all that.”
Generally, the entire technology transfer process, including equivalency studies and receiving regulatory approval, takes about a year, so Advent had a pretty good head start before we even heard about it. It also sounds like some additional developmental work, to overcome some “challenges,” has been occurring in the background related to DCVax-Direct that hasn’t been discussed yet, that Linda is alluding to.
For those that don’t know, the first challenge that Linda was taking about “related to the machine that we use for the first stage of the process,” is their proprietary tangential flow filtration system that Dr. Bosch helped to design and patent, and is used to separate the monocytes, the pre-cursors of dendritic cells, from the rest of the leukapheresis material. This technology is rather old and somewhat obsolete, and I speculate that Advent might use another system, like centrifugation, to achieve this task, as they do with DCVax-L. This may also mean that Advent will use another system to culture the cells because the previous system was all enclosed in one system.
When monocytes are cultured in flasks, well plates, or in the cartridges of the Flaskworks EDEN system, they adhere to the bottom of the pre-coated polystyrene surface, which actually begins the activation process. However, manufacturing DCVax-Direct, requires that the dendritic cells are cultured in suspension in a bagged system in order to delay the activation of the cells, so the Flaskworks EDEN system can’t be used for DCVax-Direct.
Fortunately, when Northwest Bio acquired the Flaskworks company, the purchase actually included two different manufacturing systems. Besides the MicroDEN system which uses the EDEN culturing system, the other “BATON” system cultures both dendritic cells in a cartridge, along with T-cells in suspension in bags. It’s speculation, but it’s possible that this BATON system could have been further developed to only culture dendritic cells in suspension in bags, and perhaps Advent plans to use this system for DCVax-Direct.
Now would be the perfect time to update and upgrade the manufacturing process with the Flaskworks technology while Advent is writing the new SOP’s for the manufacturing process and getting regulatory approval. This would certainly speed the commercialization process of DCVax-Direct by using the same, approved manufacturing process and equipment in clinical trials that will eventually be used for the commercial product.
The other challenge is “one which related to some key ingredients in the process.” I’ll go out on a limb here and speculate about this too, because I have previously speculated that Northwest Bio may substitute poly-ICLC for BCG in the manufacture of DCVax-Direct. Because DCVax-Direct is injected directly into the tumor, in an attempt to bypass the tumor’s defenses, activation and maturation of the dendritic cells are delayed, so it’s necessary to add an ingredient to achieve this activation later. For the first trial, Cognate used Bacillus Calmette-Guerin (BCG) and IFNy, but there are other ways to activate the cells, like TLR agonists (poly-ICLC) for example. As we all know, the combination of DCVax with poly-ICLC in trials at UCLA, have produced some astounding results, which has led to my (and others) speculation.
Anyway, I’m looking forward to the DCVax-Direct announcement and further explanation of these changes to the manufacturing process, as well as the start of the trials. Another reminder about these next trials, Linda said they will have surrogate endpoints, (tumor response ) shrinkage and necrosis will likely be seen (systemically) in weeks and months, not years. I anticipate that a DCVax-Direct announcement may occur when the MHRA has approved the tech transfer, hopefully before the end of the year.
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