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Combining vaccines and adoptive T cell transfer for breast cancer immunotherapy
Tumor Cell Biology III
Background: Anti-cancer T cells generated by genetic modification of patient lymphocytes are a promising means of specific, effective therapy for breast cancer. Previous work has demonstrated that adoptive transfer of gene-modified CD4+ T cells in addition to CD8+ T cells armed with a gene specific for the breast cancer-associated antigen Her-2 can impact on lung metastases in mice. In addition, using a separate strategy, anti-tumor effects could be achieved by adoptive transfer of CD8+ dual-specific T cells that recognize both tumor and an allogeneic immunogen. However, large established tumors were refractory to these treatments alone. In this proposal, we wish to combine these approaches into one powerful immunotherapy strategy targeting established primary and metastatic Her-2-expressing tumors in immunocompetent transgenic mice expressing human Her-2 in some normal tissues. This model will allow us to investigate several important issues that have remained unresolved to date: which include persistence of gene-modified T cells, impact of the endogenous immune system on therapy and possible therapy-mediated autoimmune effects. The results of this study will validate this novel therapy for testing in future Phase I clinical trials. Hypothesis: Adoptive transfer of dual-specific T cell subsets in combination with a viral vaccine will cause regression of breast cancer. Specific aims: 1) Test the anti-tumor potential of combining adoptive transfer of dual-specific T cells and viral vaccine in Her-2 transgenic mice. 2) Investigate the mechanism of T cell activity against metastatic disease, and the role of different T cell subsets. 3) Investigate important regulatory and toxicity parameters of therapy in Her-2 transgenic mice. Study design: In Aim 1, investigations will be performed to determine whether transfer of dual-specific CD8+ and CD4+ T cells and immunization can impact on breast tumor growth in Her-2 transgenic mice. In Aim 2, we will test the importance of various effector molecules/cytokines to the anti-tumor effect using donor T cells from gene targeted, mice and examine the importance of various dual-specific CD4+ T cell subsets (Th1, Th2) in combination with dual-specific CD8+ T cells in vivo. In Aim 3, we will investigate several parameters for optimization of this strategy in mice. This will involve determining (i) the effect of the endogenous immune system (eg. Treg cells) on the activity of dual-specific T cells; (ii) the effect of non-myeloablative conditioning on the therapy; (iii) whether transferred T cells may induce autoimmunity. Potential outcomes: Adoptive transfer of dual-specific T cell subsets with diverse functional abilities, and a powerful vaccine to induce activation and expansion of these cells, may result in an important new therapy option for breast cancer patients.
The aim of this project is to develop a new treatment for breast cancer that uses the body?s own immune system against cancer cells. The immune system is extremely good at protecting us against infectious disease, and vaccines are able to boost this protective ability. Viral vaccines protect us by the stimulation and multiplication of specialized anti-virus T cells (a type of white blood cell), which are very good at searching out and destroying virus-infected tissues in the body. In contrast, cancer vaccines, in their current form, are ineffective and only poorly stimulate specific anti-cancer T cells, and these do not localize to tumors. We aim to combine the search-and-destroy capability of anti-virus T cells with the specificity of anti-cancer T cells by creating dual-specific T cells that are part anti-virus and part anti-cancer. We will test this approach in mice with breast cancer. Dual-specific T cells will be produced by genetic modification of anti-virus T cells in the laboratory using a gene enabling a response against the breast cancer molecule, Her-2. The dual-specific T cells will then be returned to mice followed by injection of a viral vaccine. The vaccine should result in stimulation and multiplication of the dual-specific T cells, and if an appropriate virus vaccine is used in the right location, the T cells should localize to the tumor. A number of parts are planned to this study including the use of two different types of T cell, ?killer? and ?helper? T cells, and the use of two different virus vaccines, influenza and vaccinia. We will study the effect of dual-specific T cells and vaccine in a mouse model of breast cancer that begins in mammary tissue and spreads to lymph nodes, lungs and bone, which closely resembles the progress of human breast cancer. The molecular target of the T cells in this project will be the human Her-2 molecule, which is also present on human breast cancer. The strain of mouse used in this study has the human Her-2 molecule also present in some normal tissues including the breast, which further increases the relevance of this experimental model to the situation for breast cancer patients. The clinical use of this approach would involve the genetic modification of patients? own T cells in the laboratory followed by their transfusion back to the patient. The vaccine used after the transfusion may vary from those used in the above proof-of-principle studies in the mouse, but the theory would remain the same.