Replies to post #44606 on NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

gnawkz,

Some very small studies under way but for the most part Provenge is being used with CI.

https://clinicaltrials.gov/ct2/results?term=Sipuleucel-T&Search=Search

It still stands as the only really proven method to provide clinical benefit to patients. And part of that reason may be because it contains many more different types of DC, as well as other APCs, and as found in their natural state. This probably induces a more robust immune response. Some have criticized it as less potent because it contains less moDC but I think that view is narrow-minded. Again, it is the one form of DC containing vaccine that has proven to provide a benefit in controlled studies.

Here's a table of some combos in development:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257036/table/T2/

You may find the entire review useful:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257036/

Of relevance to DCVax-L is:

"Third, the ideal strategy for DC antigen-loading is not universally agreed upon. The most common approach has been loading with tumor-associated peptides or whole recombinant tumor proteins [1]. While these non-mutated self-antigens may break self-tolerance at the cellular level, they rarely do so at the host level [108], accounting for disappointing clinical results. Putative reasons for this phenomenon include negative selection of high-avidity clones with ensuing self-tolerance to low-avidity clones [109] and maintenance of host level self-tolerance via pre-programmed immunosuppressive elements (e.g., Treg) [108].

Strategies have been proposed to overcome these pitfalls: a) co-administration of TLR agonists, as discussed earlier [6]; b) silencing of antigen presentation “attenuators” (e.g., SOCS1) may enhance in vivo DC function by augmenting immunogenicity [108]; c) using homologous xenogeneic (e.g., murine) antigens to break self-tolerance [110]; and d) engineering DCs loaded with mutated neo-antigens from patient-specific tumors, which may activate a T-cell repertoire without pre-programmed Treg [111]. Other modalities of DC loading (engineered fusion proteins, autologous/allogeneic tumor cells, tumor cell-lysate, DC-tumor hybrids, and DNA- or mRNA-transfected) have emerged and are reviewed elsewhere."

And one example of combo with CI:

In advanced melanoma patients, co-administration of MART1-pulsed DCs and anti-CTLA-4 mAb (tremelimumab) yielded durable antitumor responses at a higher rate than with either agent alone [143]. The non-specific mechanism of CTLA-4 blockade, however, manifests as dose-limiting toxicity in many patients. Conversely, anti-PD-1 antibodies, which impair the inhibitory CTL:PD-1 ligand interaction on tumors, potentiate tumor-specific immunity and demonstrate a more favorable toxicity profile [144]. Administration of anti-PD-1 antibody (pidilizumab) enhanced activated-CTL responses following stimulation with an autologous myeloma-DC fusion vaccine [145]. Pidilizumab is currently being investigated in combination with DC vaccination in hematologic, renal, and prostate malignancies [4]

GL