Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer.

Abstract

Triple negative breast cancer (TNBC), which constitutes 10%-20% of all breast cancers, is associated with aggressive progression, a high rate of metastasis, and poor prognosis. The treatment of patients with TNBC remains a great clinical challenge. Preclinical reports support the combination immunotherapy of cancer vaccines and immune checkpoint blockades in non-immunogenic tumors. In this study, we constructed nanoparticles (NPs) to deliver an mRNA vaccine encoding tumor antigen MUC1 to dendritic cells (DCs) in lymph nodes to activate and expand tumor-specific T cells. An anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibody was combined with the mRNA vaccine to enhance the anti-tumor benefits. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone. These data support both the NP as a carrier for delivery of mRNA vaccine and a potential combination immunotherapy of the NP-based mRNA vaccine and the CTLA-4 inhibitor for TNBC.

• Authors: Lina Liu, Yuhua Wang, Lei Miao, Qi Liu, Sara Musetti, Jun Li, Leaf Huang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 1 Pg. 45-55 (01 03 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29258739 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents, Hormonal
• CTLA-4 Antigen
• CTLA4 protein, human
• Cancer Vaccines
• MUC1 protein, human
• Mucin-1
• Recombinant Fusion Proteins
• Interferon-gamma

Topics

• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Antineoplastic Agents, Hormonal (pharmacology)
• CTLA-4 Antigen (antagonists & inhibitors)
• Cancer Vaccines (genetics, immunology)
• Cell Line, Tumor
• Combined Modality Therapy
• Dendritic Cells (immunology, metabolism)
• Disease Models, Animal
• Female
• Humans
• Immunotherapy
• Interferon-gamma (metabolism)
• Lymph Nodes (immunology, metabolism, pathology)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Mice
• Mucin-1 (genetics, immunology)
• Recombinant Fusion Proteins
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Triple Negative Breast Neoplasms (drug therapy, genetics, immunology, pathology)
• Xenograft Model Antitumor Assays