Tumor Immunology and Clinical Studies


Research Project Awards



A Peptide Vaccine for Breast Cancer Prevention

Esteban Celis, M.D., Ph.D.
Cytel Corporation

Breast cancer is a serious health problem both in the US and worldwide. In the US alone approximately 182,000 new cases of breast cancer are diagnosed each year and breast cancer is the most common malignancy and the third leading cause of cancer deaths in women (46,000/year). Because most of these deaths are the result of tumor recurrences and metastatic disease, new approaches to prevent disease progression such as immune-based vaccines must be seriously considered. The purpose of this project is to define the capacity of synthetic protein fragments (peptides) to induce cytotoxic T lymphocyte (CTL) responses to antigens expressed on breast tumor cells. Because CTL are the immune cells most capable of directly killing tumor cells, vaccines that induce these immune responses are an attractive way of preventing cancer recurrences or at least inhibiting tumor progression in women with early disease. Most significantly, such vaccines could be used to prevent the occurrence of breast carcinoma in healthy women who are genetically at high risk of developing this disease. This could be accomplished by immunization of young women from families with high rates of breast carcinoma.

CTL recognize antigenic peptides derived from processed proteins which bind to major histocompatibility gene complex (MHC) molecules. The MHC molecules, also known as the transplantation-rejection antigens, are present in most cells including tumors and have the main function of presenting antigenic peptides to CTL. We aim to identify CTL antigenic peptides in a specific protein called HER2/neu, which is produced in high amounts in aggressive breast tumors. Potential CTL antigens from the HER2/neu protein have already been selected for these studies by the identification of those peptides from the protein that bind to the human MHC molecules. Following a protocol successfully utilized to identify melanoma tumor CTL antigens, we will test the MHC-binding peptides from the HER2/neu protein for breast cancer-specific CTL responses. These experiments will be done in tissue culture using blood lymphocytes from normal volunteers and breast cancer patients. The final goal of this work is to identify several peptides from the HER2/neu protein which are capable of eliciting tumor-specific CTL. The outcome of these studies will be the basis of the development of these peptides into CTL-inducing vaccines used to prevent or delay progression of breast tumors that express the HER2/neu antigen.

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Molecular Design for Prevention of Breast Cancer Progression

Joseph R. Couto, Ph.D.
Cancer Research Fund of Contra Costa

We propose to engineer a molecule that will be ideally suited for arresting metastatic progression of breast cancer. This molecule will be designed to deliver a destructive radioisotope only to breast tumor cells. Both single metastatic cells and large tumors will be efficiently targeted. When used in multiple periodic administrations, the molecule should be able to prevent the recurrence of metastatic breast cancer. Therefore, the success of this project should provide a means to reduce the mortality from breast cancer by prolonging or saving the lives of those afflicted with metastatic disease.

Our proposed iFab2 molecule will be related to "antibodies," which are natural defense molecules that find their targets with exquisite specificity. Previous human clinical trials have demonstrated the ability of antibodies (attached to radioisotopes) to target metastatic breast carcinoma cells but they also point to some problems: 1) the large size of antibodies leads to suboptimal targeting rates and to poor penetration of large tumors, and 2) antibodies can stick to healthy defense cells. This sticking is desirable in the natural situation as a means to summon defense cells to destroy foreign invaders tagged by antibodies. In the clinical setting however, this can result in the destruction of healthy cells, in diminishing the rate of delivery of the radioisotope to tumor cells, and in other undesirable side effects. The proposed iFab2s will find their targets like antibodies but will diffuse more rapidly to metastatic sites. iFab2s will also lack the regions that bind healthy defense cells while retaining the high affinity and specificity for breast tumor cells.

iFab2s do not occur naturally and cannot be prepared directly from antibodies. Essentially they will look like two connected and inverted antibody fragments. We propose to optimize their design, which will be encoded by a single engineered gene. This gene will direct the production of iFab2s for breast cancer treatment in unlimited quantities and ready for attachment to a radioisotope. The first iFab2s will have the targeting properties of our best humanized antibodies, BrE-3 and Mc3, which have been proven to target and specifically destroy human breast carcinomas. If successfully designed, these iFab2s could be used to completely arrest metastatic progression with negligible damage to non-tumor tissues.

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Peptide Vaccines for Immunoprevention of Breast Cancer

Thomas J. Kipps, M.D., Ph.D.
University of California, San Diego

This project will examine how the immune system can be used to prevent recurrent breast cancer. About a third of all women with breast cancer have breast tumor cells that make a large amount of a particular protein, called erbB-2. Because of this, these tumor cells can be distinguished immunologically from normal cells. We aim to take advantage of this distinctive feature of breast cancer cells to develop a novel strategy to treat those patients who have tumors that make large amounts of the erbB-2 protein. Our research will investigate ways to induce an immune response against this protein in such patients. Such an immune response should destroy tumor cells that make erbB-2, and thereby protect such patients from developing recurrent breast cancer.

We propose to study synthetic peptide vaccines that can stimulate an immune response against cells that overproduce erbB-2. Because erbB-2 is a self protein, it ordinarily does not stimulate an immune response. However, synthetic peptides that mimic portions of the erbB-2 protein can induce an immune response against erbB-2, particularly when such peptides are physically coupled to an immunogenic protein or presented by activated immune cells that can initiate the immune response. The immune response induced by these synthetic peptides can result in the production of antibodies that bind erbB-2. Alternatively, they may activate "helper T cells" that can induce cytotoxic T cells and/or macrophages that specifically can kill tumor cells. We have identified candidate synthetic peptides that can induce such responses and have developed methods for identifying additional synthetic peptides for use as vaccines against recurrent breast cancer.

We plan to: 1) characterize the antibodies induced by synthetic peptides of erbB-2 for their ability to affect adversely the growth or survival of breast tumor cells; 2) identify synthetic peptides of erbB-2 that can be presented to, and recognized by, helper T cells; and 3) examine peptide vaccines for their ability to prevent breast cancer recurrence. Through these studies we may discover effective strategies for the active immune prevention of recurrent breast cancer.

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Innovative Developmental and Exploratory Awards (IDEAs)


Blocking Breast Cancer Progression with Radioactive Antibody

Michael Samoszuk, M.D.
University of California, Irvine

Approximately 20% of human breast cancers are extensively infiltrated by a rare type of white blood cell called an eosinophil and contain extracellular deposits of an enzyme called eosinophil peroxidase (EPO). Coincidentally, EPO has vary significant structural similarity to lactoperoxidase, an enzyme that is naturally found in breast milk and that is secreted by lactating breast cells but not by the resting breast cells. We have developed a monoclonal antibody called EOS that binds to EPO and possibly to human lactoperoxidase but not to any other normal human tissues. Based on pilot study data, we hypothesize that EPO and/or lactoperoxidase are present at high levels within small nests of breast cancer in certain patients. Consequently, we propose that EOS antibody will be an ideal vehicle for specifically delivering radioactive materials to the EPO/lacto-peroxidase target within the nests of breast cancer. The radioactive material will then damage or destroy the cancer cells and blood vessels within the tumor, thereby preventing the progression of the cancer without causing significant systemic toxicity.

In order to test this hypothesis, we first intend to retrieve up to 300 archival specimens of benign breast conditions and breast cancers of different types. These tissue specimens will be tested for the presence of EPO and/or lactoperoxidase. We will then chemically attach EOS antibody to rhenium-188. This radioisotope was selected because it has a short half-life, does not accumulate in normal tissues, and can be effectively administered at low doses. Following the radio labeling, we will determine the physical properties of the radioactive antibody to determine if it will be suitable for human use. When completed, these preclinical feasibility studies will translate into a compelling rationale for initiating subsequent clinical trails of rhenium 188-EOS, a novel radiopharmaceu-tical that will have value for preventing disease progression in a subset of breast cancer patients whose tumors contain EPO deposits or lactoperoxidase.

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