Abstract B113: Development of a novel synthetic consensus DNA vaccine that targets multiple MAGE-A family members for anticancer immune therapy

Abstract

Abstract Cancer/testis (CT) antigens have emerged as attractive targets for cancer immune therapy due to their overexpression in tumor tissues and lack of expression in normal tissues. In particular, several clinical studies have been initiated to target the MAGE-A family of CT antigens for melanoma. These have included recombinant protein immunization and TCR-based gene therapy for MAGE-A3. The recombinant protein immunizations resulted in poor CD8+ T-cell responses and lack of efficacy thus far in the clinic. TCR-based gene therapy induced robust immune responses but unexpected toxicity. There is therefore a need to develop safe and effective therapies targeting the MAGE-A family of proteins for cancer therapy. In this study we performed a thorough analysis of MAGE-A RNA expression in The Cancer Genome Atlas (TCGA) and demonstrated that a high proportion of patients, in particular patients with melanoma and lung squamous cell carcinoma, exhibit expression of multiple MAGE-A family members simultaneously within the same tumor sample. Based on this information, we designed a consensus MAGE-A DNA vaccine that retains high homology (>85%) to multiple MAGE-A isoforms. Because mice and human MAGE-A family members are poorly conserved, we designed separate consensus constructs for testing in mice and in primates. Upon delivery of this mouse consensus MAGE-A vaccine intramuscularly followed by electroporation (EP) in C57Bl/6 mice, we detected robust IFN-γ and TNF-α CD8+ T-cell responses against multiple MAGE-A isoforms, including MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A5, MAGE-A6, and MAGE-A8 (p<0.005). Furthermore, we detected robust cytotoxic CD107a/IFN-γ/T-bet triple-positive CD8+ T cells in mice immunized with the consensus mouse MAGE-A vaccine. We evaluated the potency and cross-reactivity of this consensus mouse MAGE-A DNA vaccine in genetically diverse, outbred mice. We found that the majority of these mice (14/15) were capable of mounting a cross-reactive immune response and breaking tolerance to multiple MAGE-A isoforms simultaneously. We also demonstrated that this consensus mouse MAGE-A DNA vaccine is capable of slowing tumor growth in a therapeutic tumor challenge using the YUMM1.7 melanoma tumor model and the TC-1 lung tumor model. These results support the use of optimized MAGE-A consensus vaccines for cancer immune therapy. Citation Format: Elizabeth K. Duperret, Aspen Trautz, Megan Paik, Charles Reed, Jian Yan, David B. Weiner. Development of a novel synthetic consensus DNA vaccine that targets multiple MAGE-A family members for anticancer immune therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B113.