Generation of a Suppressor tRNA-Mediated Antitumor Immune Response to Treat Ovarian Cancer
Abstract
In developed countries, ovarian cancer is the deadliest gynecological cancer and the fifth most common cancer-related cause of death in women. In the United States, age-adjusted mortality due to ovarian cancer has decreased by 23% over the past four decades, but this decrease in age-adjusted mortality is the result of a reduced incidence of ovarian cancer, it is not a result of improved treatment options. In fact, 12-year survival rates have stayed unchanged. This is not necessarily surprising because treatment of ovarian cancer has remained largely the same: surgical debulking, followed by chemotherapy. An important reason for the poor prognosis of ovarian cancer is that, most often, it is diagnosed at late stages (stage III or IV) when the tumor has already heavily metastasized, primarily into the abdomen (peritoneal cavity). As a result, the 5-year survival rates are dismal, especially for stage IV ovarian cancer where the 5-year survival rate is only 17%. Consequently, the identification of conceptually novel approaches to treat ovarian cancer is central to the mission of the Department of Defense Ovarian Cancer Research Program (OCRP). More recently, so-called immunotherapy has been added to arsenal of weapons against ovarian cancer. As the name indicates, the goal of immunotherapy is to stimulate the patient s own immune system to destroy the ovarian tumor and metastasis. However, the high incidence of all types of cancer indicates that our immune system struggles to prevent tumor growth. Considering the "traditional" role of our immune system, this is not really unexpected. Over millions of years, our immune system has evolved to defend us against pathogens such as bacteria and viruses. But, whereas it is the immune system s job to destroy pathogens, it is equally important that the immune system does not attack our own body. Put differently, our immune system must be able to distinguish between self and non-self. Although tumors are made up of "abnormal" cells, they are still mostly recognized as self by our immune systems and are, therefore, not efficiently attacked by it. The ultimate goal of cancer immunotherapy is to "teach" the immune system to recognize the tumor as non-self and to destroy it, and here we propose a novel method to achieve this. In an approach similar to vaccinations against viruses, one approach that is being tested in immunotherapy against cancer is the injection of tumor cells that have been irradiated to prevent them from growing after injection. The premise of this approach is that the injection of irradiated tumor cells will trigger an immune response against the tumor and metastasis themselves. However, for this to be successful, the irradiated tumor cells that are injected must be recognized as non-self. It is in fact the case that compared to their non-cancerous counterparts, some tumor cells express mutated proteins that can potentially be recognized by the immune system as non-self. In turn, these mutated proteins can give rise to an immune response against the tumor. However, the number of mutated proteins is usually very low, and the mutated proteins are often near-identical to their natural versions. As a result, the immune system struggles to recognize them as non-self, which, in part, explains the poor immune response. Here, we propose to coax the tumor cell s protein synthesis machinery to create a large number of elongated versions tumor proteins. Because the novel "protein tails" created by our approach have never been produced by any cell in the body, they will be recognized as non-self by the immune system and are expected to raise a strong immune response. It is well known that once a strong initial immune response is raised against one or several proteins, it can induce an immune responses against additional proteins of a tumor. Hence, we anticipate that our method will result in an immune response against a large number of tumor proteins.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610128
Entities
People
- Thomas Weber
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army