A Multiantigen Vaccine Targeting EMT-Associated Proteins to Prevent Recurrent Ovarian Cancer
Abstract
In the last decade we have come to better understand the important role the immune system plays in helping eradicate cancer. The components of the immune system that are needed to kill cancer are T-cells: CD8 T-cells which can directly kill the tumor and CD4 T-cells that secrete certain cytokines called Type I cytokines (such as interferon-gamma (IFN-g)) that assist the CD8 T-cells in working more effectively. Taken together, this type of immune response is called a Type I immune response, and many studies have now shown that the presence of a Type I immune response in the tumor is associated with a better clinical outcome and may predict those cancer patients who respond to immunotherapy with immune checkpoint inhibitors. Nearly every patient has evidence of an immune response against their tumor. However, most do not have a Type I immune response. The majority of patients with cancer, including ovarian cancer, have a dominance of Type II T-cells, which are responsible for the generation of a primary antibody response to cancer. Most of the tumor-specific antibodies generated by exposure to the tumor do not bind well to the cancer and have no effect on tumor growth. Strategies are needed to increase the level of Type I T-cells in ovarian cancer. We believe that this can be done with a multi-antigen cancer vaccine designed specifically to stimulate Type I T cells. What class of protein antigens would we target with an ovarian cancer vaccine? There are many types of proteins that are immunogenic in ovarian cancer. One type is proteins that have a mutation in their sequence. These proteins are encoded from mutated genes. In cancers such as melanoma, which is highly mutated, these proteins, when used in vaccination, can generate high levels of Type I immunity. Mutated proteins are not common in patients with ovarian cancer. More common immunogenic proteins are non-mutated tumor antigens that are abnormally expressed during the cancer process. These proteins are weakly immunogenic, and the immune system, while recognizing the proteins are abnormal, makes an ineffective response—one that will not destroy the cancer. Work from our group has shown that we can overcome the barrier to successful immunization against non-mutated cancer-causing proteins. We have identified small sections of cancer-related non-mutated proteins, called “epitopes,” which are processed by our immune system and only stimulate Type I CD4 T-cells (Th1) that can secrete inflammatory cytokines that support the development of CD8 killer T-cells. We can identify these segments though a combination of computer modeling and functional screening. Immunization with only Th1-selective epitopes generates high levels of unopposed Type I immunity; both Th1 and killer T-cells in the blood and in a number of animal models results in markedly increased CD8 tumor infiltrating lymphocytes (TIL) and a potent anti-tumor effect. What specific proteins would we include in an ovarian cancer vaccine? Ideally, we would want to prime the immune system to eradicate the most dangerous tumor cells, and those would the kind that cause metastases or are able to avoid being killed by chemotherapy. These factors are characteristic of ovarian cancer cells that have undergone a process called epithelial to mesenchymal transformation or EMT. The presence of cells that have undergone EMT in the tumor of ovarian cancer patients is associated with a poor prognosis and poor response chemotherapy. Cells that have undergone EMT upregulate non-mutated proteins that are involved in driving this process forward. We have identified several of these proteins as immunogenic in ovarian cancer patients and suitable to be vaccine candidates. Specifically, we have chosen four proteins: IGFBP-2, IGF-IR, HIF1a, and surviving, which are all implicated in the development of EMT and drug resistance. One, or a combination, of these proteins can be found in nearly every ovarian cancer
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110389
Entities
People
- Mary Disis
Organizations
- United States Army
- University of Washington