Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial

Gabriel I Nistor,Robert O Dillman

doi:10.1186/s12967-020-02328-6

Abstract

BackgroundIn a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.Methods110 proteomic markers were measured at a week-0 baseline, 1 week before the first of 3 weekly vaccine injections, and at week-4, 1 week after the third injection. Data was presented as a deviation from normal controls. A two-component principal component (PC) statistical analysis and discriminant analysis were performed on this data set for all patients and for each treatment cohort.ResultsAt baseline PC-1 contained 64.4% of the variance and included the majority of cytokines associated with Th1 and Th2 responses, which positively correlated with beta-2-microglobulin (B2M), programmed death protein-1 (PD-1) and transforming growth factor beta (TGFβ1). Results were similar at baseline for both treatment cohorts. After three injections, DCV-treated patients showed correlative grouping among Th1/Th17 cytokines on PC-1, with an inverse correlation with B2M, FAS, and IL-18, and correlations among immunoglobulins in PC-2. TCV-treated patients showed a positive correlation on PC-1 among most of the cytokines and tumor markers B2M and FAS receptor. There were also correlative changes of IL12p40 with both Th1 and Th2 cytokines and TGFβ1. Discriminant analysis provided additional evidence that DCV was associated with innate, Th1/Th17, and Th2 responses while TCV was only associated with innate and Th2 responses.ConclusionsThese analyses confirm that DCV induced a different immune response than that induced by TCV, and these immune responses were associated with improved survival.Trial registration Clinical trials.gov NCT004936930 retrospectively registered 28 July 2009

Highlights

In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines (TCV)
TCV consisted of irradiated autologous tumor cells from a short-term cell line; DCV consisted of autologous dendritic cells incubated with irradiated autologous tumor cells [8, 9]
Both DCV and TCV were admixed in granulocyte-macrophage colony stimulating factor (GM-CSF) just prior to subcutaneous injections scheduled for weeks 1, 2, 3, 8, 12, 16, 20, and 24

Summary

Introduction

In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. An early analysis showed that DCV was associated with better survival [8], and this was confirmed when 5-year follow up showed a more than doubling of median survival and 3-year survival rate, and a 70% reduction in the risk of death [9] This DCV approach is currently being tested in phase II trials in glioblastoma and ovarian cancer, and in a phase IB trial in combination with monoclonal antibodies to programmed death-1 protein (PD-1) in melanoma patients

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Conclusion