NorthWest Biotherapeutics Inc (NWBO)

[Evaluate]

The DCVax-L process involves straining cells at the right maturity level from bone marrow. DNDN had a high level of the wrong cells in their collection, which made it less effective. NWBO has perfected that process. Even while in the midst of this trial, they improved the collection of immature cells so that more patients would have enough DCs to be in the trial. Then, they needed to mature the DCs to the correct level of maturity. This is very difficult. I have forgotten some of this process, but my memory is that L is matured outside the body where it is introduced to specific stimuli that is their secret source, then is injected back into the body fully matured.
Direct is also introduced to stimuli outside the body, then injected into the body as immature DCs where they finish their maturity after taking up cancer cells from the tumor they have been injected into.

I believe that with Direct, the DCs that are administered back into the patient are partially matured.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093019/
includes:

DCVax®-Direct. This platform is used in the context of unresectable solid tumors that cannot provide adequate autologous tumor for preparation of DCVax-L. While the DCVax-Direct platform starts with leukopheresis to obtain autologous monocytes which are then differentiated into DCs, these DCs are not fully differentiated in vitro but rather stimulated in vitro with bacillus Calmette-Guerin for a short time to induce DC activation, but unlike the more mature DCs, these activated or partially matured cells do not express CD83, a well-known maturation marker that was shown to provide co-stimulatory signals [17]. These activated DCVax-Direct DCs are injected unpulsed into the tumor where they are thought to take up autologous solid tumor in situ and then mature with production of IL-12 p70 and CD83 with MHC class II molecules and present these antigens to the immune system.

DCVax-Direct is currently in a Phase I/II dose-escalation vaccine composed of direct intratumoral injection of partially matured autologous DCs injected into the tumor, either directly or utilizing image guidance

https://www.firstwordpharma.com/node/1107719
includes:

The key to DCVax-Direct is the use of partially matured dendritic cells. These specially prepared dendritic cells have the ability to pick up tumor antigens (i.e., tumor biomarkers) from tumor cells inside the tumor after the dendritic cells are directly injected into the tumor. After picking up the antigens, these dendritic cells also have the ability to travel to lymph nodes and mobilize the immune system to attack tumors throughout the body which express these antigens. NW Bio holds strong patent coverage on both the manufacturing processes and the use of such partially matured dendritic cells.

NWBO: Program Update ASCO June 2 2019
includes:

• DCVax-Direct is comprised of partially activated,
autologous dendritic cells for intra-tumoral injection
– Partially activated DC retain the capability to take up antigen,
and are irrevocably committed to full maturation
• In preclinical work, optimally activated DC were
meaningfully more effective in clearing established
tumors than immature DC

&

• The system initially produces fully immature DC
– Consequentially, one has full control over the DC activation
process
– To produce DCVax-Direct, the cells are partially activated, retain antigen uptake capability, and progress irrevocably to fully mature DCs that induce an immune response
• The potency of the produced DC, e.g. measured by cytokine
production, is significantly enhanced

Clinical Trials: Immunotherapy
Published OnlineFirst July 17, 2018; DOI: 10.1158/1078-0432.CCR-17-2707
Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers

Another consideration in DC-based immunotherapy is DC
maturation.
Immature DCs take up antigens more readily; however, they also induce T-cell tolerance by triggering apoptosis, promoting anergy, or priming regulatory T cell (Treg) differentiation in T cells (12). To ensure that the exogenously loaded DCs will elicit an active immune response, maturation agents must be used during vaccine preparation, either before or after antigen loading (10, 13).
Maturation agents include Toll-like receptor (TLR) agonists or mixtures of cytokines, such as tumor necrosis factor a (TNFa), interleukin (IL)-1b, IL6, and prostaglandin E2 (PGE2; ref. 10). Differentiation protocols often include IL4 to inhibit differentiation into macrophages instead of DCs (14), but
this is not required if monocyte activation is avoided during
purification (15).
Some strategies supplement their maturation compounds with interferon g (IFNg), IFNa, and polyinosinic: polycytidylic acid to generate mature type-1–polarized DCs that secrete IL12. The mature DCs induce a T-helper cell 1 (TH1)-type profile that elicits natural killer cell and CTL activation (16, 17).
CTL activation triggers a proinflammatory state, stimulating these
cells to kill tumor cells directly