Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer

Abstract

See Covering the Cover synopsis on page 862. BACKGROUND & AIMS:Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor, and patients typically present with late-stage disease; rates of 5-year survival after pancreaticoduodenectomy are low. Antibodies against ␣-enolase (ENO1), a glycolytic enzyme, are detected in more than 60% of patients with PDA, and ENO1-specific T cells inhibit the growth of human pancreatic xenograft tumors in mice. We investigated whether an ENO1 DNA vaccine elicits antitumor immune responses and prolongs survival of mice that spontaneously develop autochthonous, lethal pancreatic carcinomas. METHODS:We injected and electroporated a plasmid encoding ENO1 (or a control plasmid) into Kras G12D /Cre (KC) mice and Kras G12D /Trp53 R172H /Cre (KPC) mice at 4 weeks of age (when pancreatic intraepithelial lesions are histologically evident). Antitumor humoral and cellular responses were analyzed by histology, immunohistochemistry, enzyme-linked immunosorbent assays, flow cytometry, and enzyme-linked immunosorbent spot and cytotoxicity assays. Survival was analyzed by Kaplan-Meier analysis. RESULTS: The ENO1 vaccine induced antibody and a cellular response and increased survival times by a median of 138 days in KC mice and 42 days in KPC mice compared with mice given the control vector. On histologic analysis, the vaccine appeared to slow tumor progression. The vaccinated mice had increased serum levels of anti-ENO1 immunoglobulin G, which bound the surface of carcinoma cells and induced complement-dependent cytotoxicity. ENO1 vaccination reduced numbers of myeloid-derived suppressor cells and T-regulatory cells and increased T-helper 1 and 17 responses. CONCLU-SIONS: In a genetic model of pancreatic carcinoma, vaccination with ENO1 DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival. This vaccination strategy might be developed as a neoadjuvant therapy for patients with PDA.

Blockade of Surface Alpha-Enolase (ENO1) as a Novel Immunotherapeutic Approach in Pancreatic Cancer

“…ENO1-specific T cells spared normal keratinocytes in in vitro cytotoxic assay [20] and no autoimmunity event nor side effects were detected after DNA-vaccination [21] or anti-ENO1 mAb treatment [13] in mice. This suggests that both ENO1-DNA vaccine and anti-ENO1 mAb therapy are safe.…”

“…This prompted us to propose ENO1 as a therapeutic candidate owing to its ability to induce an integrated humoral and cellular response. We developed a DNA vaccination to ENO1 in genetically engineered mice (GEM) that spontaneously develop autochthonous, lethal pancreatic cancer [21], and we showed that the vaccine significantly induced a specific immune response against pancreatic tumors, which efficiently prolonged mouse survival. We demonstrated that ENO1 DNA vaccination induced a specific antibody as well as a cellular response in mice.…”

“…We demonstrated that ENO1 DNA vaccination induced a specific antibody as well as a cellular response in mice. Notably, DNA vaccination elicited anti-ENO1 IgG binding at the surface of GEM-derived PDA cells, which killed them by inducing a complement-dependent cytotoxicity (Figure 1 central panel) [21]. Furthermore, ENO1 DNA vaccination reduced the numbers of peripheral and intratumoral myeloid-derived suppressor cells (MDSC) and T-regulatory cells and increased T-helper 1 (Th1) and Th17 responses.…”

Pancreatic cancer vaccine: a unique potential therapy

“…Of clinical relevance, the therapeutic efficacy of the ENO1 DNA vaccine was observed to be very promising when the administration protocol started at 8 months to 9 months of age. 107 In these mice, the ENO1 DNA vaccine also induced the formation of intratumoral tertiary lymphoid tissue (TLT) with active germinal centers and correlated with increased recruitment of T-cells. 108 Analysis of human PDA tissues by immunohistochemistry revealed two distinct patterns of B-cell distribution, either as randomly infiltrating cells (CD20-tumor-infiltrating …”

Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation

“…DNA-based vaccination against human ENOA is able to significantly prolong the median life expectancy of mice that spontaneously develop PDAC, by inducing both a humoral and cellular response [27].…”