Survival benefit of RCC vaccine
Authors: Melanie Clyne
Journal: Nature Reviews Urology (2012)

Encouraging clinical trial data for IMA901-the first therapeutic vaccine for renal cell carcinoma (RCC)-have been published online by Nature Medicine.This vaccine has been given to a total of 96 human leukocyte antigen A (HLA-A)*02-positive patients with advanced clear-cell RCC in phase I (n = 28) and phase II (n = 68) trials, resulting in improved disease control and overall survival with minimal adverse effects.Walter and colleagues designed the vaccine using an antigen discovery platform called XPRESIDENT, which combines mass spectrometry, gene expression profiling, in vitro cell assays, functional assessment, and bioinformatics to identify multiple tumour-type-specific tumour-derived peptides (TUMAPs).In the phase I study, the majority (about 75%) of patients demonstrated a vaccine-induced response to at least one TUMAP and almost a third responded to multiple TUMAPs.Patients who responded to multiple peptides were significantly more likely to exhibit disease control (stable disease or partial response) than those who responded to one TUMAP or had no response."Patients achieve greater clinical benefit if they are able to mount immune responses to multiple peptides in the IMA901 vaccine, confirming the hypothesis that a broad simultaneous attack of the immune system on multiple targets is beneficial," says a senior investigator for the study, Harpreet Singh-Jasuja.Following on from these early data, an aim for the subsequent phase II trial was to identify an agent that could reduce numbers of regulatory T cells, which counteract the anti-tumour responses associated with cancer vaccination.In this randomized open-label multicentre trial, a single intravenous infusion of cyclophosphamide prior to the first vaccination with IMA901 reduced numbers of regulatory T cells and was associated with improved overall outcomes.Although no difference in progression-free survival was evident between the two patient groups, cyclophosphamide treatment was associated with a significant improvement in overall survival (25.3 months versus 14.8 months).This effect was only observed in patients with specific immune responses to IMA901, suggesting that cyclophosphamide acts as a vaccine immunomodulator.In the second trial, Walter et al. also identified two serum biomarkersapolipoprotein A-1 and chemokine (C-C motif) ligand 17-that could help to predict response to IMA901 and identify patients with the greatest chance of achieving overall survival benefit."The current (ongoing) pivotal phase III trial with IMA901 aims to confirm that these two biomarkers are predictive of improved overall survival," Singh-Jasuja remarks.By the end of 2012, the investigators hope to recruit approximately 330 patients to this trial, which includes sunitinib-the standard first-line therapy for RCC-to decrease numbers of myeloid-derived suppressor cells.Patients are randomized to receive sunitinib, either with IMA901 vaccine (plus immunomodulators) or alone.The primary endpoint of the trial is overall survival, but a key secondary endpoint is overall survival in a prospectively defined biomarker-positive subgroup."The first results from this study are expected in 2014," predicts Singh-Jasuja."If all goes according to plan, the vaccine could be available to patients with advanced RCC by 2016."Importantly, although standard-of-care therapies for RCC have been shown to reduce tumour growth, they have had little effect on survival to date."From a clinical point of view, the further development of active immunization in combination with a low dose of one-off chemotherapy is a significant step in the treatment of kidney cell carcinoma," says Arnulf Stenzl, the principal investigator for both trials, "and possibly for the treatment of other malignant tumours as well."Thus, these study findings might have relevance for research into other cancer vaccines."The principle applied here-of active immunization against cancer antigens previously identified in cancer cells-can be applied to treat practically all types of cancer," adds Hans-Georg Rammensee, a renowned pioneer in the field of cancer immunology.