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

Abstract

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. 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. 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 <i>Tyr::CreER;BRAF^Ca/+;Pten^lox/lox</i> transgenic mice that develop melanoma upon tamoxifen induction. The MAGE-A DNA therapeutic vaccine significantly slowed tumor growth and doubled median mouse survival. 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.