Wistar Scientists Develop Improved DNA Vaccine Targeting the Tumor Microenvironment
PHILADELPHIA — (Dec. 21, 2017) — Today, scientists at The Wistar Institute announced that they have developed a novel synthetic DNA vaccine targeting fibroblast activation protein (FAP), a protein that is highly expressed in the tumor microenvironment. The tumor microenvironment protects cancer cells from the host immune system, allowing them to survive and expand, causing progressive disease. The new synthetic FAP vaccine improved anti-tumor activity in combination with another DNA vaccine that directly targets the tumor cells in pre-clinical studies, illustrating a major benefit of this two-pronged approach for cancer immunotherapy. The study was published online in Clinical Cancer Research.
"We utilized a novel technology developed in our laboratory for synthetic DNA vaccine optimization," said lead researcher David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. "This work demonstrates the potential of this dual approach for hitting the cancer’s protective niche in the tumor microenvironment as well as taking out the cancer itself. Our strategy provides a double-fist punch for targeting difficult cancers."
Immune and stromal cells in the tumor microenvironment establish immune suppressive conditions that nourish and shield the cancer cells, presenting a major obstacle for the success of cancer immunotherapy, which traditionally targets only the cancer cells. Therefore, combined strategies that focus both on the tumor and the destruction of the tumor microenvironment appear to increase the impact of immunotherapy approaches.
FAP is absent in most normal tissues and its expression is restricted to fibroblasts responding to pathologic conditions such as wound healing, fibrosis and coopted by cancer. Furthermore, FAP expression is increased in cancer-associated fibroblasts (CAFs) that are known to promote tumor immune evasion.
Weiner and colleagues used the synthetic consensus (SynCon) strategy, previously developed by their team, to design a novel DNA vaccine in which the FAP gene sequence was modified to render it more visible to the immune system, allowing for improved immune recognition. The SynCon FAP vaccine proved superior to the non-modified sequence in generating higher and more diverse cellular immune responses against the native FAP.
The team also evaluated the therapeutic efficacy of the SynCon FAP vaccine in combination with DNA vaccines targeting tumor cells in mouse models of lung and prostate tumors and found that combined immunization generated a more robust anti-tumor activity, extended tumor control and improved mouse survival compared to either immunotherapy alone.
Mechanistically, the team observed that the SynCon FAP vaccine induced killer T cell activity both in the spleen and at the tumor site in immunized mice, as demonstrated by increased production of functionally protective T cell-specific molecules.
The study included a detailed analysis of FAP expression in cancer patients in correlation with clinical outcome and immune composition of the tumor microenvironment. In accordance with previous studies, Weiner’s team found that high levels of FAP correlate with poor patient survival as well as enhanced macrophage infiltration and decreased T cell infiltration, both of which are characteristic of an inflammatory, immune suppressive environment that is more permissive to tumor growth.
"Our work further details that FAP is a bad actor in cancer and extends prior work further establishing that FAP is a viable therapeutic vaccine target for cancer immunotherapy, with particular efficacy when used in combination with vaccine therapy that targets tumor cells," commented Elizabeth Duperret, Ph.D., a postdoctoral researcher in the Weiner Lab and first author of the study.
This work was supported by NIH/NCI Fellowship F32 CA213795, NIH SPORE grant P50CA174523 to Wistar and the University of Pennsylvania, as well as funding from the W.W. Smith Charitable Trust, the Basser Foundation, and Inovio Pharmaceuticals.
Co-authors of this study from The Wistar Institute include Aspen Trautz, Dylan Ammons, and Alfredo Perales-Puchalt. Other co-authors include Megan C. Wise, Jian Yan, and Charles Reed from Inovio Pharmaceuticals, Inc.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.