Dataset Information

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

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 Tyr::CreER;BRAF^Ca/+;Pten^lox/lox 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.

SUBMITTER: Duperret EK

PROVIDER: S-EPMC6319943 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Duperret Elizabeth K EK Liu Shujing S Paik Megan M Trautz Aspen A Stoltz Regina R Liu Xiaoming X Ze Kan K Perales-Puchalt Alfredo A Reed Charles C Yan Jian J Xu Xiaowei X Weiner David B DB

Clinical cancer research : an official journal of the American Association for Cancer Research 20180927 23

<h4>Purpose</h4>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<sup>+</sup> T-cell immunogenicity, platform toxicity, or perhaps limited target antigen availability. In this study, we develop an improved MAGE-A immunogen with cross-reactivity t ...[more]

PMID: 30262507

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Project description:Breast cancer is the second leading cause of cancer-associated mortality among women worldwide, and the prevalence and mortality rates associated with this disease are high in Western countries. The melanoma-associated antigen (MAGE) family proteins are well-known tumor-specific antigens; this family includes >60 proteins that serve an important part in cell cycle withdrawal, neuronal differentiation and apoptosis. The aim of the present study was to identify a biomarker within the MAGE family that is specific for breast cancer. In the present study, the prognostic role of MAGE mRNA expression was investigated in patients with breast cancer using the Kaplan-Meier plotter database. The prognostic value of MAGE members in the different intrinsic subtypes of breast cancer was further investigated, as well as the clinicopathological features of the disease. The results of the present study indicated that patients with breast cancer that had high mRNA expression levels of MAGEA5, MAGEA8, MAGEB4 and MAGEB6 had an improved relapse-free survival, whereas those with high mRNA expression levels of MAGEB18 and MAGED4 did not. These results suggested that MAGEA5, MAGEA8, MAGEB4 and MAGEB6 may have roles as tumor suppressors in the occurrence and development of breast cancer, whereas MAGEB18 and MAGED4 may possess carcinogenic potential. MAGED2, MAGED3 and MAGEF1 had different effects depending on the type of breast cancer. In particular, high MAGEC3 mRNA expression was associated with worse RFS in lymph node-positive breast cancer, but with improved RFS in lymph node-negative breast cancer. In patients with wild-type TP53 and patients with different pathological grades of breast cancer, MAGEE2, MAGEH1 and MAGEL2 were more worthy of attention as potential prognostic factors. The results of the present study may help to elucidate the role of MAGE family members in the development of breast cancer, and may promote further research that identifies MAGE-targeting reagents for the treatment of breast cancer.

Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

Similar Datasets

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