NorthWest Biotherapeutics Inc (NWBO)

[hyperopia]

speaking of patents; did anyone notice the number of new and pending patents in the 10-K ? To refresh your memory:

During 2020, three new patents were issued to us as part of our worldwide patent portfolio. The newly issued patents cover methods for manufacturing dendritic cells related to our DCVax products, as well as encompassing certain methods of use and compositions that may be potential future markets related DCVax products. Additionally, with the addition of Flaskworks, the Company gained one issued patent and eight pending patent applications.  In addition, the Company gained the rights to an another issued patent and 15 pending patent applications that Flaskworks had exclusively licensed from Northeastern University.  Collectively these patents and patent applications cover key aspects of the design and function of automated cell culture systems.

The first point is that the manual process of producing dendritic cells that Cognate and Northwest Bio optimized for DCVax-L, and used for the clinical trials and compassionate use, is currently being translated into an automated, commercial process. I thought that Northwest Bio might also have Cognate establish a commercial process modifying established automated manufacturing systems, but it appears that Linda wants to own all the intellectual property for both the equipment and commercial process. When the equivalency studies are completed and approved, Northwest Bio will have the only patented, and approved device and process for generating clinically meaningful dendritic cells for commercial production. That seems far more valuable than some previous patents on a manual process that might expire.

Second point, re-read that last sentence and note the plural: "Collectively these patents and patent applications cover key aspects of the design and function of automated cell culture systems."
Flaskworks has patented two automated systems. The other device, the BATON, that seems to be overlooked, is capable of co-culturing two types of cells simultaneously; adherent cells (dendritic cells) and suspension cells (T-cells). Pretty brilliant system in my opinion. In an interview back in 2018, Shashi Murthy describes it:

Can you give us a sense of the role played by dendritic cells in cell and gene therapy and immunotherapy?

SM: Dendritic cells have come a long way in immunotherapy. Because immunotherapy relies on addressing short-circuiting of the immune system by cancer, the use of these cells is already quite widespread in discovery of biologics and characterization of biologics in immunotherapy. However, with the advent of cell-based immunotherapy, the first approved therapy was PROVENGE, and that was many years ago. However, the technology associated with cell-based immunotherapy for cancer using dendritic cells has come a long way, and I think that we're on the cusp of seeing a number of more sophisticated therapies directed in a very targeted way against different challenging indications in cancer.

But the other side to this is that there's another frontier altogether of using dendritic cells to prepare and manufacture exquisitely-targeted T-cell therapies based on neoantigens for example, and I think there, they are poised to play an equally important role. Even though they're not therapies themselves, they'll play a role in the manufacturing of those autologous therapies, and I think that's an important frontier not only for immunotherapy of cancer but also in the manufacturing realm.

The BATON is described and pictured here:

Co-culturing different cell types

In the next generation of T-cell cancer therapies, the T cells will have a library of molecules on their surfaces, and these molecules will recognize and target tumor-specific neoantigens. Bespoke T-cell therapies will be generated by selecting the patient’s own T cells against libraries of neoantigens. After the neoantigens are acquired by sequencing the tumor, they will be presented by the patient’s own dendritic cells (DCs). Because DCs are not abundant in circulating blood, they are typically prepared by first differentiating them from monocytes.

DCs and T cells may be co-cultured, but suitable instrumentation is required, says Shashi Murthy, PhD, professor of chemical engineering at Northeastern University. At the time this article was written he was scheduled to describe the design of such instrumentation at the Cell and Gene Therapy Bioprocessing and Commercialization conference.

“DCs so generated are adherent cells, and T cells are suspension cells,” Murthy explains. “So, you have to design a bioprocess to generate adherent cells and then be able to co-culture that adherent cell type with a suspension cell type. “At the end of that process, you’re recovering the suspension cell type only. Further adding to the complication is the fact that this type of stimulation will sometimes need to be done in multiple cycles, [requiring] a fresh supply of DCs that are stimulated with a different batch of antigens.”

To keep T cells happy, instrumentation may incorporate a polystyrene-bottomed surface for optimized generation of DCs; a perfusion apparatus consisting of a tubing set; and a vessel with adequate headspace and perfusion-mediated gas exchange. “It’s sort of a hybrid between static vessels and gas-permeable bags,” Murthy says. “It’s all a closed system.”

According to Murthy, fully integrated automated systems are very capable but too expensive to adopt at the preclinical stage. “A lot of work is done manually and then translated into such systems,” he notes. “Now there’s a move in the industry to try to build closed systems that are sufficiently robust for clinical manufacturing and provide the benefits of automation, but at the same time are affordable enough to integrate into preclinical and Phase I environments.”

At Northeastern University, Shashi Murthy, PhD, and colleagues have developed the Bioreactor for Autologous T-Cell Stimulation (BATON) system. Featuring a highly modular design and incorporating fully disposable components (including disposable pumps and on-board reagent storage), BATON is designed to reduce manual operations in the co-culture of dendritic cells and T cells for neoantigen-based therapies. The system is being commercialized by a spinout called Flaskworks.


https://www.genengnews.com/insights/knocking-the-rough-edges-off-t-cell-therapy-manufacturing/