In a strategy that may prevent tumors from eluding the immune system's attack, researchers have developed a new cancer vaccine capable of targeting multiple members of a cancer-causing family of proteins at once.
Because proteins in the melanoma-associated antigen (MAGE-A) family are highly tumor specific and are overexpressed in several types of cancer, they have become a focus of recent immunotherapy research efforts. Yet melanoma and lung carcinoma investigations of MAGE-A3, a MAGE-A isoform that has the highest expression in several solid tumors, have had limited success for a variety of reasons, including an inability to provoke a strong immune response in cytotoxic T cells, toxicity of the delivery platform, or possibly limited availability of the target antigen. In a new breakthrough, researchers at The Wistar Institute have developed an improved MAGE-A vaccine that has cross-reactivity to 7 members of the MAGE-A family, enabling it to promote immune responses against multiple tumor antigens at once.
When the researchers analyzed MAGE-A expression in The Cancer Genome Atlas (TCGA), a US government-funded project that uses genomic sequencing and bioinformatics to catalogue genetic mutations responsible for cancer, they noticed that for many tumors, patients often simultaneously expressed multiple MAGE-A isoforms, not just MAGE-A3. For this reason, they developed an optimized consensus DNA vaccine that could react with a wide variety of MAGE-A isoforms.
When tested in an autochthonous model of melanoma induced in mice using tamoxifen, the vaccine produced strong immune responses against multiple MAGE-A isoforms and generated a cross-reactive immune response in 14 of 15 genetically diverse, outbred mice. The vaccine also slowed tumor growth substantially and doubled median survival.
"The combination of structural design and synthetic DNA technology offers ample flexibility and specificity in the development of a designer target immunogen," commented study senior author David B. Weiner, PhD, executive vice president of The Wistar Institute, director of the Institute's Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. "This vaccine is recognized by the host immune system much more robustly, resulting in improved immune performance."
Elizabeth K. Duperret, PhD, first author on the study and postdoctoral fellow at The Wistar Institute, emphasized the clinical relevance of the results: "Patients whose tumors express multiple members of this family of antigens represent an important group to study the benefits of this immunotherapy approach."
For More Information
Duperret EK, Liu S, Paik M, et al (2018). A designer cross-reactive DNA immunotherapeutic vaccine that targets multiple MAGE-A family members simultaneously for cancer therapy. Clin Cancer Res. [Epub ahead of print] DOI:10.1158/1078-0432.CCR-18-1013