Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma

Lisa H Butterfield, Lazar Vujanovic, Patricia M Santos, Deena M Maurer, Andrea Gambotto, Joel Lohr, Chunlei Li, Jacob Waldman, Uma Chandran, Yan Lin, Huang Lin, Hussein A Tawbi, Ahmad A Tarhini, John M Kirkwood, Lisa H Butterfield, Lazar Vujanovic, Patricia M Santos, Deena M Maurer, Andrea Gambotto, Joel Lohr, Chunlei Li, Jacob Waldman, Uma Chandran, Yan Lin, Huang Lin, Hussein A Tawbi, Ahmad A Tarhini, John M Kirkwood

Abstract

Background: Cancer 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.

Methods: Based 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.

Results: The 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.

Conclusions: DC 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 registration: NCT01622933 .

Keywords: Cancer vaccine; Immune biomarkers; Melanoma; Shared antigens; Tumor immunity.

Conflict of interest statement

Consent for publication

All authors confirm that they have no relevant conflicts of interest to report.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Kaplan-Meier plot of OS and PFS. a and b. OS and PFS is shown for patients who were randomized after DC vaccines (n = 23) to observation (no boost, n = 12 randomized + 2 not receiving HDI) or those randomized to HDI (n = 11 randomized, 9 receiving IFN). OS: IFN vs. OBS p = 0.54 (ns). PFS: IFN vs. OBS p = 0.43 (ns). Not shown are those who progressed early, before randomization (n = 12), who were the statistically significant different clinical group vs. those randomized (OS p = 0.0001, PFS p < 0.0001)
Fig. 2
Fig. 2
IFNγ ELISPOT assay for purified CD8+ and CD4+ T cells. A direct ELISPOT was performed to determine the frequency of T cells specific to full length antigens expressed in autologous DC and previously characterized peptides (n = 28 patients). Assay controls (no antigen, PMA + ionomycin) are also shown. The circle symbols denote trial arm, and the responses of the two PR patients are also noted (filled triangle)
Fig. 3
Fig. 3
Whole blood T and NK cell phenotyping. a-f The percentages and absolute counts for CD3+CD4+ and CD3+CD8+ T cells expressing naïve/effector/memory markers (CD45RA, CCR7) (a-c) or trafficking markers (CXCR3, CCR6) (d-f) are shown in melanoma patients (n = 35 patients) in comparison to HD controls (n = 35) (a, b) or by trial arm (d, e). Box plots for significant correlations with clinical response are shown (c, f, j). g-i NK cell subset phenotyping for NKG2D expression levels as shown for HD and patients
Fig. 4
Fig. 4
Circulating suppressor cell frequencies. The frequencies of (a) Treg and subsets of myeloid (b, c) MDSC are shown (n = 35 patients). The left side of each panel shows the difference between baseline and d = 43 post DC vaccines. The right side of each panel shows the change between d43 and d89 for each trial arm. Dotted lines represent median HD values (n = 35). Two examples of significant correlations between MDSC frequencies and patient development of vaccine antigen-specific T cell responses are shown (d)

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