New Strategy for the Redirection of Cytolytic T Lymphocytes to Breast Tumors.

摘要

The main objective of this research project has been to apply the T- body approach for the immunotherapy of breast cancer. To this end, we endowed human lymphocytes with anti-erbB2 specificity by transducing them with a tripartite chimeric receptor made of anti-erbB2 scFv-linked through the homeo- domain, trans membrane and endo-domain of cD28 to the cytoplasmic region of the FcR-gamma chain. In this report we describe an improved protocol for the preparation of a retrovector harboring the chimeric gene and efficient expression of this transgene in human T cells. The ability of the tripartite chimeric receptor to fully activate primary T cells was demonstrated in vitro and in vivo using transgenic mice made with a model receptor. Transgenic mice that express erbB2-specific receptor have been generated and the ability of it's lymphocytes to reject erbB2 expressing tumors will be tested. To avoid tumor escape chimeric receptors of two scFv's from different antibodies were prepared. Using breast cancer xenografts we started to test the anti-tumor potency of ERBB2-specific, genetically engineered human lymphocytes in SCID mice. In another pre clinical model, we have expressed the erbB2-specific tripartite chimeric receptor in murine stem cells and are studying their ability to mature into mature effector cells. Altogether, we expect from the model systems described above to establish the optimal conditions of using a T-bodies breast cancer therapy.