Clinical Applicability and Improved Efficacy of a CMV-Vectored Vaccine in a Heterogeneous Spontaneous HER2+ Tumor Model
Abstract
Immunotherapies have yielded impressive results in many cancers, including advanced stage melanoma, B cell leukemia, and more recently in triple-negative breast cancer. For many decades, it was thought that the immune system was primarily a bystander in cancer, but it’s now clear that the natural immune response is frequently very active in fighting cancer progression. It is in this context that interventions that either “remove the brakes” or “step on the gas” of the immune system sometimes can lead to dramatic tumor regression and/or cures, and Drs. Jim Allison and Tasuko Honjo were awarded a Nobel Prize in 2018 for their pioneering work in immunotherapy. This Expansion Award proposal continues the development of a different type of immunotherapy, a cancer vaccine, that has shown remarkable tumor regression in a genetically engineered strain of mice that develops HER2+ mammary tumors that are a close model of human HER2+ breast cancer. Approximately 52,000 women per year develop HER2+ breast cancer, representing 15%-20% of new breast cancer diagnoses. Breast cancers expressing HER2 are aggressive. Despite improved treatments, 5-year survival when metastases are detected at diagnosis is only ~40%. When there are no metastases at diagnosis, expected survival improves considerably, but frontline treatment is frequently followed by recurrence, with resistant metastases often found in the liver, lungs, and/or brain. Further, the effects of new treatments on overall survival and progression-free survival are often incremental. For example, a highly touted 2020 study in the New England Journal of Medicine showed that addition of a new kinase inhibitor, called tucatanib, improved progression-free survival in the target population by only 2.2 months. Our approach is to create a breast cancer vaccine by inserting the gene for HER2 into a common virus called cytomegalovirus, or CMV. This virus is clever in many ways. It establishes a permanent infection in most of the world’s population. Yet most people have never heard of it because it causes few symptoms. Once CMV infects a person, it never goes away. The immune system can sense the virus, and keeps CMV under a constant state of surveillance. Because of this, the immune response to CMV is extremely strong. By inserting HER2 into the virus genome, we essentially trick the immune system into thinking that this cancer-causing gene is part of the virus. When the immune system becomes activated, it devotes a lot of that effort to killing the HER2+ cancer cells. In addition, we bred a new strain of mice that develops HER2+ mammary tumors that are very similar to human HER2+ breast cancer, with prior BCRP funding. One major bottleneck to developing better treatments is to have mice that get very similar disease. Then we can study how well the vaccine works in mice, why it sometimes doesn’t work, and how to make it more successful in humans. These tumors were scored by a pathologist who categorized them as similar to several HER2+ breast cancer subtypes. Further analysis revealed that they also resembled HER2+ breast cancer at a molecular level. Finally, most tumors metastasized to the liver or lungs, meaning we can test whether our vaccine will prevent these metastases. Importantly, we show in our grant that they respond to some of the main therapies used in humans with HER2+ breast cancer, and even develop resistance to these drugs, much as some women do. We tested our CMV-HER2 vaccine in these mice, knowing that it would be a high hurdle. Importantly, tumors did not simply grow more slowly, but instead completely disappeared. Although some tumors later returned, the data exceeded our expectations. We are now seeking Expansion Award funding to develop this vaccine further towards clinical trials. The first goal of this proposal is to figure out the key differences between the majority of tumors that disappear vs. those tumors that don’t. Is it due to differences in the tumor, or d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110276
Entities
People
- Rosalie C Sears
Organizations
- Oregon Health & Science University
- United States Army