Replies to post #18937 on NorthWest Biotherapeutics Inc (NWBO)

[Evaluate]

Good questions regarding Partial Maturation.
I did a google search ("dendritic cells" & "partially mature") .... many results. I have no answers ... too medical for me to comprehend.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355325/
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Conclusion
The initially surprising finding that partially matured DCs can still act tolerogenic has now reached a broader base by numerous reports and more mechanistic insights. Semi-mature DCs can be generated in vitro and exert a distinct spectrum of tolerogenicity after injection. The finding that semi-mature ssmDCs are continuously engaged to tolerize lymph node T cells against peripheral self-antigens opens further perspectives for therapies, especially against autoimmune diseases and allergies. Thus, tolerogenic regimens employing semi-mature DCs may in the future either be concentrated on in vivo targeting with antibodies or transcutaneous antigen application regimens.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845009/
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The initial poor results of DC-based immunotherapy could be due to the immature or only partially mature phenotype of the DC, and in particular to their reduced levels of IL-12 secretion. Thus, many alternative maturation protocols have been developed, which induce DC with an enhanced IL-12 secretion and functionality in vitro, with some of them that have also reached clinical application. The “alpha type-1 polarized DC” obtained upon maturation in the presence of IL-1ß, IFN-a, IFN-?, poly IC, and TNF-a (130) have been tested in patients with recurrent glioma (131, 132), melanoma, and colorectal cancer (NCT00390338 and NCT00558051 at www.clinicaltrials.gov, respectively), whereas DC stimulated with LPS and IFN-? have been used for the treatment of patients with breast cancer (133, 134). DC stimulated with the streptococcus-derived immunotherapeutic agent OK432 have been used against hepatocellular carcinoma (135) and colorectal cancer (136).
In parallel to the manipulation of the maturation protocol, the type of DC was also optimized. Alternative differentiation protocols for monocytes have been tested to obtain more physiologic DC types.

www.edisoninvestmentresearch.com/?ACT=18&ID=11140
Interesting report
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We have written extensively on the rapidly burgeoning field of cancer immunotherapy. This is a broad field covering a number of classes of agents – vaccines, DC-based vaccines, adoptive T-cell therapies, immune checkpoint inhibitors – and the inherent potential (and proven with some
approved products) of this approach to treating cancer is vast. Although the bulk of current
excitement surrounds the anti-PD-1 immune checkpoint inhibitors (nivolumab/lambrolizumab/
RG7446), it is likely that DC vaccines and adoptive T-cell therapies will form an important
component of attacking cancers, particularly in combination with other agents.
An advancing technology DC vaccines are an extension of the traditional cancer vaccine approach. Dendritic cells are a type of antigen-presenting cells (APC) capable of processing antigen material and presenting it on the surface to other cells of the immune system. DC-based therapy involves isolating DCs from a patient, priming them with cancer antigen(s), before injecting them back into the patient. DC-based therapy therefore circumvents some of the limitations of the traditional vaccination approach because it more effectively presents cancer antigens to the immune system.
A DC-based vaccine, Dendreon’s Provenge, delivered one of the first successes in the cancer
immunotherapy field when FDA approval was secured for the treatment of prostate cancer in 2010.
However, Provenge is very much a first-generation DC vaccine, using immature or partially mature DCs that are suboptimal in stimulating a T-cell response. This factor, coupled with manufacturing inefficiencies and a very high treatment price, has resulted in Provenge failing to meet high initial commercial expectations. FY13 sales of Provenge were $285m, although previous consensus had been >$1bn.
Second-generation DC therapies employ mature DCs (mDCs) that are able to simulate stronger
immune responses, but the most promising candidates are so-called ‘third-generation’ DC
vaccines, which involve genetic manipulation and/or enhancement with maturation mixtures that
enhance tumour-specific T-cell responses.

opus4.kobv.de/opus4-fau/files/4036/IsabellPfeifferDissertation.pdf
also interesting.
See section 5.1.5 etc.
Immature and partially mature DC are not suitable for immunotherapy
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Taken together, the application of immature of partially mature DC into cancer patients
remains a controversial issue. In our opinion, the injection of immature DC bears a high risk
of inducing tolerance in combination with the high secretion of the immunoinhibitory IL-10.
Furthermore, the quality of the DC needs to be properly checked at the time point when the
DC are injected into the patients

[flipper44]

Gnawks, thank you soooo much for noticing this detail. I had to go back and listen to the presentation. It comes up at 28 minutes and 22 seconds on the webcast.

They tested 2 different maturation times.

Here is my best initial guess. And here, I really am guessing. As you pointed out, Linda mentioned that there can be a significant difference between 16 hours maturation, v. 20 hours, v. 24 hours.

Because they are only testing 2 different maturation times (see above), and Linda stated at (25 minutes on the webcast) "it matters" how much partial activation there is, I think they confirmed an exact maturation time they will use for future trials.

The logic here being that while Linda did not quite want to announce to the world which time works better, as you can understand phase I is still being dosed, "it matters."

My guess is, "it matters."