Tuesday, March 15, 2016

DC vaccines produced with tumor cells undergoing immunogenic cell death

Dendritic cells are the most potent activators of na├»ve T cells. A lot of effort has been spent to develop DC-based cellular vaccine. We even had some success in mouse models. But, so far no DC based vaccine worked in humans to significantly prolong patients survival. It is not surprising that only company that developed FDA-approved DC vaccine prostate cancer went bankrupt. There are many reasons as to why it is so hard. For one, there are several types of dendritic cells. Secondly, just pulsing [tumor] antigens on dendritic cells were found not to be sufficient.

Few weeks ago, Science Translational Medicine published study wherein the authors had tested next-generation tumor vaccine produced by pulsing DCs with tumor cells undergoing immunogenic cell death.

Basically, the authors had used a high-grade glioma (HGG) cell lines as a source of tumor. To generate immunogenic cell death, tumor cells were exposed to hypericin-based photodynamic therapy (Hyp-PDT). This treatment induces expression/release of several damage-associated molecular patterns (DAMPs) acting as potent danger signals for DCs. When mice were injected with DCs pulsed with Hyp-PDT treated glioma cells, they showed resistance to subsequent live glioma brain challenge.

Mechanistically, tumor protection provided by Hyp-PDT DCs depended on (1) DAMPs, (2) DC-specific MyD88, (3) CD8 T cells (T cells data are shown here).

Importantly, Hyp-PDT DC vaccines improved survival of brain tumor-bearing mice when applied therapeutically and in combination with standard-of-care therapy such as temozolomide (TMZ).

In summary, this study showed that hypericin-based photodynamic therapy could generate immunogenic tumor cells required for proper activation of DC for vaccination purpose. Conceptually, such mode of DCs preparation makes a lot of sense, but there are several technical challenges before this system could be translated into clinic, as discussed by the authors (such as, how to avoid presence of "surviving" live tumor cells within DC vaccine, route of DC vaccine injection [the authors have used intra-peritoneal injection, for some reason], what type of DC is the best for this purpose). 

David Usharauli

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