A Designer Cross-reactive DNA Immunotherapeutic Vaccine That Targets Multiple MAGE-A Family Members Simultaneously for Cancer Therapy

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2018 Sep 29

PMID 30262507

Citations 20

Authors

Elizabeth K Duperret

Shujing Liu

Megan Paik

Aspen Trautz

Regina Stoltz

Xiaoming Liu

Kan Ze

Alfredo Perales-Puchalt

Charles Reed

Jian Yan

Xiaowei Xu

David B Weiner

Affiliations

Soon will be listed here.

Abstract

Purpose: Cancer/testis antigens have emerged as attractive targets for cancer immunotherapy. Clinical studies have targeted MAGE-A3, a prototype antigen that is a member of the MAGE-A family of antigens, in melanoma and lung carcinoma. However, these studies have not yet had a significant impact due to poor CD8 T-cell immunogenicity, platform toxicity, or perhaps limited target antigen availability. In this study, we develop an improved MAGE-A immunogen with cross-reactivity to multiple family members.

Experimental Design: In this study, we analyzed MAGE-A expression in The Cancer Genome Atlas and observed that many patients express multiple MAGE-A isoforms, not limited to MAGE-A3, simultaneously in diverse tumors. On the basis of this, we designed an optimized consensus MAGE-A DNA vaccine capable of cross-reacting with many MAGE-A isoforms, and tested immunogenicity and antitumor activity of this vaccine in a relevant autochthonous melanoma model.

Results: Immunization of this MAGE-A vaccine by electroporation in C57Bl/6 mice generated robust IFNγ and TNFα CD8 T-cell responses as well as cytotoxic CD107a/IFNγ/T-bet triple-positive responses against multiple isoforms. Furthermore, this MAGE-A DNA immunogen generated a cross-reactive immune response in 14 of 15 genetically diverse, outbred mice. We tested the antitumor activity of this MAGE-A DNA vaccine in transgenic mice that develop melanoma upon tamoxifen induction. The MAGE-A DNA therapeutic vaccine significantly slowed tumor growth and doubled median mouse survival.

Conclusions: These results support the clinical use of consensus MAGE-A immunogens with the capacity to target multiple MAGE-A family members to prevent tumor immune escape.

Citing Articles

An Immunohistochemical Study of MAGE Proteins in Hepatocellular Carcinoma.

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PMID: 39125568 PMC: 11311968. DOI: 10.3390/diagnostics14151692.

Development of Personalized Strategies for Precisely Battling Malignant Melanoma.

Isaak A, Clements G, Buenaventura R, Merlino G, Yu Y Int J Mol Sci. 2024; 25(9).

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Advances in Therapeutic Cancer Vaccines, Their Obstacles, and Prospects Toward Tumor Immunotherapy.

Eskandari A, Leow T, Rahman M, Oslan S Mol Biotechnol. 2024; .

PMID: 38625508 DOI: 10.1007/s12033-024-01144-3.

Melanoma Antigen Family A (MAGE A) as Promising Biomarkers and Therapeutic Targets in Bladder Cancer.

Verma S, Swain D, Kushwaha P, Brahmbhatt S, Gupta K, Sundi D Cancers (Basel). 2024; 16(2).

PMID: 38254738 PMC: 10813664. DOI: 10.3390/cancers16020246.

Dysregulated Repeat Element Viral-like Immune Response in Hepatocellular Carcinoma.

Coley A, Lu C, Pankaj A, Emmett M, Lang E, Song Y bioRxiv. 2023; .

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