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Adoptive Immunotherapy for HER2 Positive Breast Cancer with Genetically Modified T Cells
Tumor Cell Biology III
Adoptive immunotherapy with T lymphocytes appears clinically effective for therapy of several malignant and infectious disorders, and transduction of T cells with artificial T cell receptors (cTCR) can potentially expand this approach by redirecting the cellular immune response to almost any surface target antigen. Despite the promise of cTCR, considerable limitations in efficacy have become evident, and it is the objective of this study to improve the function and persistence of T cells expressing cTCR directed to breast cancer cells. Our fundamental hypothesis is that T cells expressing a HER2 specific cTCR can target HER2 positive breast cancer cells and that the effectiveness of these cells can be enhanced by ensuring that T cells receive appropriate co-stimulatory signals proximate to the time of cTCR engagement. We will test this hypothesis in two specific aims. In specific aim 1 we will express "conventional" cTCRs (containing the CD3-zeta chain) in Epstein Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL). These CTL bind through their native receptor to EBV-infected B cells, which also transmit a multitude of costimulatory signals. This ensures that proliferation occurs, and that activation is sustained long enough for the CTL to be cytolytic when they recognize their tumor target through the cTCR. In specific aim 2 we will incorporate the endodomains of costimulatory molecules into cTCR. Previous reports suggested that incorporation of the CD28 endodomain in the cTCR enhanced the functionality of the modified T lymphocytes, but our experience has shown that such activation is limited. However, we have recently shown that generating a cTCR in which the CD3-zeta chain is linked to both the CD28 and OX40 endodomains produces a receptor which activates multiple signal transduction pathways in T cells, to produce high level and sustained cytokine release and cellular proliferation. In t he current proposal we will generate HER2 cTCR and compare how well EBV-CTL expressing HER2-zeta and T cells expressing HER2(CD28-OX40- zeta) enhance the function of cells modified to express these specificities. We will study the activity of the chimeric T cell variants in human ex vivo and murine xenograft tumor models. We expect at the conclusion of the grant to have established an efficient system to generate HER2-specific T cells, which not only kill HER2 positive breast cancer cells but also persist and expand in vivo, as a foundation for a clinical trial.
The long-term objective of this project is to develop an innovative, immunotherapeutic approach for breast cancer. Depending on tumor size, early stage breast cancer has a good prognosis, however long-term survivors might suffer from treatment related complications. For patients with local advanced breast cancer and/or metastatic disease the outcome remains poor. I t is therefore desirable to develop novel therapies that could improve outcomes for patients with advanced stage disease, and which might ultimately reduce the incidence of long-term treatment related complications in all patients. Cellular immunotherapies have the potential to fulfill both of these needs. This proposal aims to develop a new immunotherapeutic approach for breast cancer. We are planning to generate T cells specific for HER2, a protein that is expressed in 30% of breast cancers at higher levels than normal cells. We will generate HER2 specific T cells by introducing a so-called chimeric receptor gene into T cells. Chimeric receptors will be first optimized in the tissue culture and then tested in a small animal model of human breast cancer. We expect at the conclusion of this project to have established an efficient system for the generation of HER2-specific T cells, which not only kill HER2 positive breast cancer but also expand after infusion, as a foundation for a clinical trial.