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Dendritic cell vaccination in melanoma

Schuler, G.

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doi: 10.1097/01.cmr.0000382777.06064.63
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Many researchers have thought that therapeutic cancer vaccines will never work, but recently Dendreon Inc. has confirmed in a large phase III trial that its 1st generation dendritic cell vaccine product Provenge significantly improved 3-year overall survival in metastatic, androgen-independent prostate cancer. This result has fostered interest in the development of cancer vaccines in general and dendritic cells (DC) vaccines in particular.

We and others have been interested in the systematic development of DC vaccines which do not rely on the isolation of minute numbers of pre-existing DC found in blood but on the generation of large numbers of DC progeny from either CD34+ or more abundant CD14+monocyte precursors. Monocyte-derived DC (Mo-DC) have become the preferred approach, not only because large numbers of DC can be generated relatively simply but also because DC displaying various properties can be produced. We have intentionally focused over the past years on Mo-DC which are produced by transforming monocytes into immature DC by GM-CSF+IL-4, followed by exposure to inflammatory cytokines and PGE2 to yield mature, immunostimulatory DC. The generation of such 2nd generation DC vaccines is now highly standardized and straightforward, yielding usually 500 million clinical grade Mo-DC from one apheresis in a closed system. Our Mo-DC were exogenously loaded with initially one and later several short tumour peptides and have been extensively tested in a series of clinical trials in melanoma patients to judge their toxicity, immunogenicity and potential clinical effect. The DC vaccine was clearly immunogenic, but side effects were minimal (constitutional symptoms, rash, vitiligo). Interestingly, a favourable clinical course (>24 months survival) in stage IV melanoma patients was observed in patients who developed significant CD4+ and CD8+ T cell responses and displayed a ‘good’ transcriptome signature in pre-vaccination metastases. This supports the hypothesis that it is the tumour microenvironment which finally decides whether significant immunity can transform into a clinically visible effect or not in such patients.

After extensive preclinical evaluation we are currently exploring mature DC, which are loaded with antigen by electroporation with mRNA. The RNA transfection technology is particularly suited to optimize DC vaccines, as besides antigen loading it can be used to produce what we call 3rd generation ‘designer’ DC vaccines e.g. by introducing homing molecules (to guide DC after i.v. injection from blood to lymph nodes) or immunostimulatory molecules (such as CD40L or CD70) to further enhance the quantity and/or quality of vaccine-induced immune responses. Ex vivo generated DC provide many opportunities to address variables in a controlled fashion to enhance vaccine efficacy. Such highly immunogenic DC vaccines will not only teach us a lot about how the human immune system operates, but should also help to achieve clinical efficacy if responsive patients can be selected by appropriate markers (e.g. transcriptome analysis of the tumor microenvironment) and/or such highly immunogenic vaccines can at last be combined with strategies to interfere with immunosuppressive circuits.

© 2010 Lippincott Williams & Wilkins, Inc.