Novel DNA Vaccine Generates Immunity Against Tumor Vasculature Protein in Preclinical Study
Researchers from the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania have employed a novel DNA vaccine that indirectly kills cancer cells by targeting a protein found in the tumor vasculature. The vaccine also indirectly creates an immune response to the tumor itself, amplifying the effect by a phenomenon called epitope spreading. The results of the study were published this month in the Journal of Clinical Investigation.
Previous studies have targeted tumor angiogenesis; however, this approach can also interfere with normal processes involved in wound healing and development. The researchers were able to avoid this pitfall by designing a DNA vaccine that specifically targets TEM1 (tumor endothelial marker 1), a protein that is overexpressed in tumors and poorly expressed in normal tissues.
“We demonstrated that by targeting TEM1, our vaccine can decrease tumor vascularization, increase hypoxia of the tumor, and reduce tumor growth,” said Andrea Facciabene, PhD, Research Assistant Professor of Obstetrics and Gynecology and a faculty member in the Ovarian Cancer Research Center at Penn Medicine. “Our results confirm that we were directly targeting the tumor vasculature and also indirectly killing tumor cells through epitope spreading.”
Study Details
The investigators injected mice with a DNA fusion vaccine called TEM1-TT, created by fusing TEM1 complementary DNA with a fragment of the tetanus toxoid (TT). In mouse models of three cancer types (breast, colon, and cervical), tumor formation was delayed or prevented in mice vaccinated with the TEM1-TT DNA vaccine. Specifically, they found that the mouse tumors had suppressed growth, decreased tumor vessel formation, and increased infiltration of immune cells into tumors.
The researchers found that the DNA vaccine, after killing the endothelial cells that make up the tumor vasculature, also resulted in epitope spreading, meaning that the immune cells of the mice gathered pieces of dead tumor cells (due to hypoxia) to create a secondary immune response against the tumor itself. The vaccine induced specific T cells to fight tumor cells expressing other proteins, in addition to TEM1, thus increasing its therapeutic efficacy.
Promising New Approach
The new DNA vaccine approach to fight cancer is showing great potential compared to previous studies that focused on tumor cells rather than the blood vessels that allow tumor cells to thrive.
“Until now there have been a lot of clinical trials using DNA vaccines to target tumors themselves, but unfortunately the results have been disappointing,” Dr. Facciabene noted. “This is a different approach, which should heighten optimism for cancer vaccines in general. Moreover, based on what we’ve seen in our mouse studies, this vaccine doesn’t seem to show any significant side effects.”
The prevalence of TEM1 in a wide range of tumor types coupled with its scarcity in normal vessels makes it a suitable target both for a prophylactic defense against cancer and a complement to other therapies such as radiotherapy and chemotherapy. “Using this vaccine simultaneously with radiation may eventually have a double synergy,” Dr. Facciabene said. “Both treatments affect the tumor endothelium, [and] radiotherapy could help the phenomenon of epitope spreading induced by the TEM1-TT vaccine.” In addition to ongoing preclinical work with human TEM1, the investigators are planning to move on to phase I human clinical trials.
The authors suggested that TEM1 may also be an excellent target as a prophylactic cancer vaccine for individuals who have a high risk of developing ovarian cancer, such as carriers of the BRCA1/2 mutations. As a bona fide vaccine, TEM-TT DNA vaccine generates a memory immune response, which Dr. Facciabene said is an ideal attribute for high-risk populations.
Dr. Facciabene is the corresponding author of the Journal of Clinical Investigation article.
The study was supported by the Basser Research Center for BRCA, the Alliance for Cancer Gene Therapy, the NIH Director's New Innovator Award, and the Pennsylvania Department of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
