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, Gabriel I Nistor, Robert O Dillman

Abstract

Background: 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. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.

Methods: 110 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.

Results: At 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.

Conclusions: These 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.

Trial registration: ClinicalTrials.gov NCT00436930.

Keywords: Cancer vaccines; Dendritic cells; Discriminant analysis; Metastatic melanoma; Principal component analysis; Proteomics.

Conflict of interest statement

GIN and ROD are both employees of AVITIA Biomedical, Inc.

Figures

Fig. 1
Fig. 1
Principal component analysis of baseline serum cytokine levels. Component loading plot of baseline serum protein levels for (a) all 39 patients regardless of treatment arm (n = 39). (KMO = 0.719; BTS < 0.001), At baseline the 22 TCV-treated patients (b) and the 17 DCV-treated patients had similar, distribution of cytokine associations
Fig. 2
Fig. 2
Principal component analysis of cytokine changes after 3 weekly vaccine injections. After 3 injections there was a noticeable difference in the distribution of cytokines between a TCV-treated patients and b DCV-treated patients with much tighter clustering in component 1 of the DCV-treated patients
Fig. 3
Fig. 3
Discriminant analysis of changes in cytokine levels after three injections and survival groups. Distribution of TCV survival groups (a) using discriminant analysis of inflammatory cytokines (Wilks’ Lambda p = 0.015). The function coefficients accurately classified all 22 patients into the appropriate survivor subgroup: 9 in the low survival group, 8 in the intermediate survival group, and 5 in the 60+ month survival group. Distribution of DCV survival groups (b) using discriminant analysis of inflammatory cytokines (Wilks’ Lambda p = 0.020). The function coefficients accurately classified the survivor subgroups: 6 in the low survival group, 6 in the intermediate survival group, and 5 in the 60+ month survival group. Distribution of DCV survival groups (c) discriminant analysis using the most powerful discriminators, TGFβ1 and IL17 (Wilks’ Lambda p = 0.003). The function coefficients accurately classified 70.6% (12/17) in the appropriate survivor subgroups: 4 of 6 in the low survival group, 5 of 6 in the intermediate survival group, and 3 of 5 in the 60+ month survival group
Fig. 4
Fig. 4
Correlation between baseline IgM and survival. a TCV-treated patients, p = 0.006 by ANOVA; b DCV-treated patients, p = 0.970 by ANOVA)
Fig. 5
Fig. 5
Linear regression analyses of selected cytokines with overall survival. a IL17 and survival in DCV-treated patients who survived less than 60 months, p = 0.028 by ANOVA; b IL12p70 and IL17 in DCV-treated patients who survived less than 60+ months, p < 0.0001 by ANOVA; c IFNγ and IL17 in DCV-treated patients who survived less than 60+ months, p = 0.001 by ANVOVA, and d TNFα and IL17 in DCV-treated patients who survived less than 60+ months, p = 0.003 by ANOVA
Fig. 6
Fig. 6
Linear regression for selected cytokines and survival by treatment. a Changes in IL17 and survival in TCV-treated patients who survived less than 60+ months, p = 0.034 by ANOVA; b changes in TGFβ1 and IL17 in TCV-treated patients who survived less than 60+ months, p = 0.012 by ANOVA; c changes in IL12p70 and TNFα after three DCV injections, p < 0.001 by ANOVA; d changes in IL12p70 and TNFα after TCV treatment, p = 0.776 by ANOVA
Fig. 7
Fig. 7
Infographic summary of findings

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Source: PubMed

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