Mechanism of CMV Vaccine Vectors Therapeutic Efficacy in a Spontaneous Model of Mammary Cancer
Abstract
Several therapies, known as immunotherapeutics, have recently been developed that unleash the immune response to tumors and have had remarkable success in treating several different cancer types. The immune system has the unique ability to continue to recognize and control residual disease after conventional treatments and hence is likely a critical component of therapies to prevent death from metastatic disease. To date, no immunotherapeutics have been approved for breast cancer. This proposal is to test an experimental immunotherapeutic in a new mouse model for human breast cancer. About 25% of human breast cancers overexpress the protein HER2, which drives an aggressive form of cancer. The mouse model developed by partnering Principal Investigator Rosalie Sears is a sophisticated genetic model in which expression of the cancer causing genes HER2 and myc are induced by lactation and expressed only in the mammary gland. Most mice then spontaneously develop breast tumors, many of which metastasize. The tumor behavior, gene expression, and pathological characteristics faithfully mimic human HER2+ breast cancer. We will use this advanced, relevant model to test our vaccine. The common virus cytomegalovirus (CMV) has many attractive features for use as a vaccine vector to initiate immune responses to other viruses and to tumors, and has been used, for example, in an experimental AIDS vaccine. This project uses CMV to express HER2 to create a vaccine that will elicit immune responses to HER2 and be used to treat mice with mammary gland tumors that express HER2. The Sears lab at Oregon Health and Science University has developed a new mouse model for mammary gland tumors that uses genetic engineering to enable tumors to spontaneously develop from a single cell in mouse mammary glands. These tumors express HER2, and look and behave like HER2-positive breast cancers in humans. We have treated six mice with small spontaneous tumors with our CMV-HER2 vaccine, and in five mice the tumors disappeared completely. One tumor resumed growth months later, and two mice later developed a second primary tumor. All mice that received CMV without HER2, or that were not treated at all, had rapid disease progression. This was a dramatic response to a single shot of the vaccine. We are now seeking funds to perform larger experiments that will give us the information we need to develop this vaccine as a human therapeutic. Differences between mice and human CMVs and mammary cancers mean that we need to create a separate vaccine for use in humans, based on the knowledge we will gain from this clinically relevant mouse model. We need to understand the relative roles of the virus vector itself and the different immune responses in causing tumor regression: this will guide specific decisions about the way the human vaccine will be constructed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710069
Entities
People
- Rosalie C Sears
Organizations
- Oregon Health & Science University
- United States Army