Abstract
BackgroundCancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects.MethodsBased on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8+ and CD4+ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation.ResultsThe resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8+ and CD4+ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8+ and CD4+ T cell subsets in clinical responses.ConclusionsDC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC.Trial registrationNCT01622933.
Highlights
Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication
Nine were grade (G)1 toxicities attributed to the Dendritic cell (DC) vaccine injection while the other 9 (2 x G2, 6 x G3, 1 x G4) were attributed to IFNα (Additional file 2: Table S3)
Our results indicate that [1] the DC based AdV vaccine is immunogenic in the population of advanced and multiply treated patients tested here, and [2] that the addition of HDI to the DC vaccine did not augment either vaccine antigen-specific T cell frequencies detected, nor the clinical responses induced by the DC vaccine
Summary
Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Immunologic vaccine interventions are ideal given their tumor specificity and potential applicability at earlier stages of disease, but new vaccine designs and combinations are needed to improve the induction of an immune response and its durability. Promotion of in vivo crosspresentation has been identified by us and others as an important element of vaccine design to optimize clinical outcomes [10,11,12,13] and may be an important mechanism for broadening the tumor antigens responded to [14], potentially including patient-specific mutated antigens, to combat tolerance, host regulatory responses and tumor antigen loss. We and others have found that induction of determinant (or “antigen” or “epitope”) spreading correlates with the development of complete clinical response and improved survival of melanoma [15,16,17,18,19,20,21]
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