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Multiple antigen-engineered DC vaccines with or without IFN? to promote antitumor immunity in melanoma.

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 IFN? 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 IFN? 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 IFN? did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC. TRIAL REGISTRATION:NCT01622933 .

SUBMITTER: Butterfield LH

PROVIDER: S-EPMC6480917 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Butterfield Lisa H LH Vujanovic Lazar L Santos Patricia M PM Maurer Deena M DM Gambotto Andrea A Lohr Joel J Li Chunlei C Waldman Jacob J Chandran Uma U Lin Yan Y Lin Huang H Tawbi Hussein A HA Tarhini Ahmad A AA Kirkwood John M JM

Journal for immunotherapy of cancer 20190424 1

<h4>Background</h4>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.<h4>Methods</h4>Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8<sup>+</sup> and CD4<sup>+</sup> T cell response against three shared melanoma antigens. The 35 vaccine recipien ...[more]

PMID: 31014399

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Project description:BackgroundBRAF(V600E)-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAF(V600E) melanoma can be increased by its combination with BRAF-I.MethodsBRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF(V600E) metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05.ResultsThe IFNAR1 level was statistically significantly (P < .001) lower in BRAF(V600E) primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination.ConclusionsThe described results provide a strong rationale for the clinical trials implemented in BRAF(V600E) melanoma patients with BRAF-I and IFNα combination.

Dataset Information

Multiple antigen-engineered DC vaccines with or without IFN? to promote antitumor immunity in melanoma.

Publications

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

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