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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Development of a multi-epitope mRNA vaccine targeting tumor-associated antigens for esophageal squamous cell
Henghui Zhang1,2, Hao Liang3,4, Tingting Dai5
1Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. zhhbao@ccmu.edu.cn.
Abstract:
Esophageal squamous cell carcinoma (ESCC) has limited treatment options post-immune checkpoint inhibitor (ICI) resistance. We developed IPM514, a universal multi-epitope mRNA lipid nanoparticle (LNP) vaccine targeting tumor-associated antigens identified via transcriptomic analysis of TCGA/GTEx datasets and validated in 132 ESCC patients. IPM514 contains 15 fragments from 9 antigens, covering most patients and over half of HLA subtypes. Peripheral blood mononuclear cells (PBMCs) from healthy donors and ESCC patients stimulated with IPM514 effectively expanded specific T cells that exhibited significant cytotoxic activity against ESCC and other squamous cell carcinomas with similar antigen profiles. In HLA-transgenic mouse models, IPM514 suppressed tumor growth, extended survival, and provided durable protection. Importantly, combination therapy with PD-1 blockade augmented antitumor efficacy by promoting immune cell infiltration, upregulating antigen presentation pathways, and reprogramming the tumor microenvironment toward an anti-tumorigenic state. These results demonstrate IPM514 represents a promising novel mRNA vaccine strategy for improving ESCC immunotherapy.
Insights
A novel mRNA vaccine, IPM514, targets esophageal squamous cell carcinoma (ESCC) by stimulating T cells. Combination therapy with PD-1 blockade enhances its anti-tumor effects, offering a promising new immunotherapy strategy for ESCC.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Esophageal squamous cell carcinoma (ESCC) presents limited therapeutic avenues following resistance to immune checkpoint inhibitors (ICIs).
- Novel strategies are crucial to overcome treatment resistance and improve patient outcomes in ESCC.
Purpose of the Study:
- To develop and evaluate IPM514, a universal multi-epitope messenger RNA (mRNA) lipid nanoparticle (LNP) vaccine, as a potential immunotherapy for ESCC.
- To assess the efficacy of IPM514, both as a monotherapy and in combination with PD-1 blockade, in preclinical models.
Main Methods:
- Transcriptomic analysis of TCGA/GTEx datasets identified tumor-associated antigens for IPM514 vaccine design.
- IPM514, containing 15 antigen fragments, was used to stimulate peripheral blood mononuclear cells (PBMCs) in vitro.
- Efficacy was evaluated in HLA-transgenic mouse models and through combination therapy with PD-1 blockade.
Main Results:
- IPM514 vaccination induced specific T cell expansion with cytotoxic activity against ESCC cell lines.
- In mouse models, IPM514 demonstrated significant tumor suppression, prolonged survival, and provided durable protection.
- Combination therapy with PD-1 blockade enhanced anti-tumor efficacy, immune cell infiltration, and antigen presentation.
Conclusions:
- IPM514 is a promising mRNA vaccine candidate for ESCC immunotherapy.
- The combination of IPM514 with PD-1 blockade shows augmented anti-tumor responses and warrants further clinical investigation.
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