Replies to post #22257 on NorthWest Biotherapeutics Inc (NWBO)

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Some interesting tidbits in that article (Author is @ Kings College, London; penned prior to Germany being added to phase III trial locations & prior to trial enhancement to 348 patients etc), such as:

re: DCVax®-L phase I and II clinical trials:

The long-term data analysis (last updated in July 2011) showed that 33.0% of patients had reached or exceeded a median survival of 48.0 months and 27.0% had reached or exceeded a median survival of 72.0 months. By year 2013, two (n=2) of the Phase I/II clinical trial patients were still alive reaching a survival of more than 10.0 years.

re: Phase I and II clinical trials on other DC-based vaccines:

Mean overall survival (OS) ranged between 16.0 and 38.4 months for ND-GBM and between 9.6 and 35.9 months for recurrent GBM. Of interest, Ardon et al.47 analyzed their results based on RPA classification and reported a mean OS of 39.7 months on patients with ND-GBM for RPA class III. Thus, it seems that specific subgroups of GBM patients may benefit from DC-vaccinations greater than others.

Re: Phase III trial:

Additional sites are due for activation and are in varying stages of preparation in the U.K. and Germany.

It would be nice to get an update on additional European sites sometime soon too.

Of note in the trial PFS and OS times are estimated from time-point of randomization, which happens approximately three months after initial surgery, whereas in common clinical practice these are usually calculated from the time of surgery.

During each session patients are administered two ID injections of either the vaccine or placebo in their upper arm. Entry into the trial is contingent on having sufficient tumor removed such that at least 5 vaccination sessions are possible. Vaccinations take place at days 0, 10 and 20 and at weeks 8, 16, 32, 48, 72, 96 and 120, depending on the patient’s clinical condition and the number of vaccine doses that have been manufactured. In the case of <10 vaccination doses available, patients are injected for the remaining vaccinations with placebo while maintaining the blind.

So some of the patients in the treatment group may not receive 10 vaccinations (but at least 5), and still remain in the treatment group despite the additional injections being placebo injections.

In case the primary and secondary endpoints are not achieved, it is planned for the data to be analyzed further based on sub-classification of the trial population. Finally, three interim analyses have been scheduled to take place for data evaluation while the trial is ongoing.

Re: Production:

Approximately two weeks after an uneventful operation the patient undergoes a session of leukapheresis, during which peripheral blood mononuclear cells are obtained. Then the cells get ex vivo differentiated to DCs with the addition of interleukin-4 (IL-4) and GM-CSF.
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If sufficient tumor lysate has been extracted, a significant amount of vaccines can be produced, which will be available for the patient as a course of treatment. Usually at least five (n=5) doses of the vaccine are required.

Immune monitoring of the product
Accurate immuno-monitoring assays/techniques to evaluate response to vaccinations are yet to be developed and uniformly used. ...
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Currently the most valid indicator of vaccination-induced immune responses to GBM is considered to be tumor infiltration by activated T cells.

Presently in the U.K. the product may be offered to a limited quota of patients on a compassionate basis outside the trial.

Final approval of DCVax®-L will await the outcome of the phase III trial although if interim analysis results are favorable, then an early approval of the product may well be achieved.

A potential disadvantage of the DCVax®-L technology could be that the use of whole tumor lysate, potentially containing healthy brain tissue, may result in immune responses against normal brain leading to autoimmune encephalitis. Presently however preliminary data from DCVax®-L and other active DC-immunotherapy trials have not revealed any SAEs related to autoimmunity. Additionally DC cancer vaccines in general may prove to be not as robust and durable as required to vanquish the intrinsic ability of cancers to suppress the immune system. Long term data is required to shed light on this view point.

Conclusion
The lack of significant improvement in the prognosis of patients with GBM in the recent years warrants exploration of new therapeutic avenues. DCVax®-L as an autologous active DC-immunotherapy agent has achieved promising outcomes with little side effects in phase I/II trials. The ongoing phase III trial is aimed at verifying these preliminary results, which if achieved, will have a major impact in the management of patients with GBM.