Only select initial trials used DC derived from CD34+ cells, perhaps a result of a more difficult production process 36. All the various trials are difficult to compare due to a range of differences, but the immunogenicity of mature DC was obvious, and hints for clinical efficacy have been observed. The first vaccine with proven clinical benefit (Dendreon’s Sipuleucel-T, Provenge™) is, however, not based on highly enriched ex vivo isolated or in vitro generated DC, but is a cellular

vaccine prepared by isolating via gradient centrifugation a DC-precursor-enriched fraction from apheresis products, which is exposed for 2 days to a fusion protein consisting of GM-CSF and prostatic acid phosphatase antigen. This results in targeting to the GM-CSF receptor-expressing cells, including DC precursors, which then undergo Anti-infection Compound Library activation/maturation in vitro (leading to CD54 upregulation which serves as a potency marker 37). Dendreon has

recently confirmed in its pivotal phase III study (IMPACT trial, n=512) that its first-generation cellular vaccine product Sipuleucel-T (Provenge™) significantly improved overall survival (by a median of 4.1 months, reducing the risk of death by 22.5% compared to the control group) in asymptomatic or minimally symptomatic metastatic, hormone-refractory prostate cancer even though classical regressions did not occur and time to progression was not prolonged 38. The result of the IMPACT BVD-523 manufacturer trial led to the approval by the FDA of the first therapeutic cancer vaccine ever on April 29th, 2010. The positive outcome has already fostered interest in the development of cancer vaccines in general and DC in particular. The Dendreon story is interesting in several aspects. It reflects,

for example, that in the cancer research community until recently the classical acute response criteria developed for chemotherapy were considered indispensable in judging vaccine effectiveness, even though it Carbohydrate had been pointed out early in the 1990s that vaccines require time but not necessarily classical regressions to produce clinical benefit 39. In 2007, the Cancer Vaccine Clinical Trial Working Group came up with an important position paper proposing a new clinical development paradigm for cancer vaccines 40, and phase II trials employing anti-CTLA-4 antibodies also unraveled distinct response patterns associated with favorable survival 41. The Sipuleucel-T product development – a nerve-wracking roller coaster – also shows that one may succeed with a product that for practical reasons has not been extensively optimized (e.g. to better enrich DC) as long as it can be reproducibly manufactured, a potency marker is available, and one has chosen a tumor amenable to the cancer vaccine.