Growing evidence suggest that human breast tumors express antigens that are recognized by the host immune system. One of these putative antigens is p 185HER2 which is encoded by the Her-2/neu proto-oncogene, belongs to the EGF receptor family and is over expressed in about 30 percent of human breast carcinoma. Antibodies directed to p185HER2 are inhibitory to the growth of breast tumors and of transformed cells that overexpress this receptor. Moreover, cytolytic T-cell with specificity to Her2/neu-associated peptide have also been detected. These findings raise a potential for immunotherapeutic intervention in patients with metastatic breast cancer that selectively target antibody-defined or T-cell-defined tumor- associated antigens. Chimeric receptors have been recently constructed and contain the variable regions of antibodies joined to the constant regions of the T-cell receptor (TCR) or of the single transducing subunit of an IG receptors (i.e.FcR). These constructs combine the exquisite antigens specificity of antibody molecules, with the homing, tissue penetration, and potent target cell destruction of immune effector cells. In an attempt to substantially increase the frequency of breast tumor antigen-reactive immune effector cells, attempts will be made to introduce genes (via retroviral vectors) encoding chimeric TCR with specificity to p185HER2 into hematopoietic stem/progenitor cells (denoted HSC). This strategy will attempt to endow progeny lineages (myeloid, lymphoid) derived from the gene modified HSC with specificity to human breast cancer following transplant and subsequent hematolymphoid reconstitution.
The Specific Aims of this application are. Insert the genes encoding the chain (s) of a functional chimeric TCR recognizing p185HER2 -overexpressed by significant proportion of human breast cancer-into a highly enriched population of human HSC: To determine whether chimeric TcR gene transfer adversely effects the ability of HSC to self renew and to give rise to progeny myeloid and lymphoid cells by both in vitro (methylcellulose), long term bone marrow cultures, and thymic organ cultures) and in vivo (SCID-hu mice) assays. To determine the function (by cytokine release in cytotoxicity) of the expressed chimeric TcR transgenes in progeny lymphoid and myeloid cells introduced at the HSC level against p185HER2 expressing human breast cancer cell lines. Conduct a phase 1 clinical trial that transplantation of chimeric TcR gene modified HSC in patients with advanced breast cancer.
| Yang, Jianmin; Friedman, Michael S; Bian, Huimin et al. (2002) Highly efficient genetic transduction of primary human synoviocytes with concentrated retroviral supernatant. Arthritis Res 4:215-9 |
