CD19 is selectively expressed on most B cell malignancies and normal B cells but not on blood stem cells and is therefore an attractive target for cancer immunotherapy. A retroviral vector encoding a CD19 specific single chain fragment (scFv) antibody fused to a TCR zeta chain has been developed. T cells transduced to express this artificial T cell receptor (termed 19z1) specifically lyse human CD19 (hCD19) expressing tumor cell lines in vitro. Furthermore, treatment of SCID-Beige mice bearing established systemic hCD19+ Raji tumor cells with 19z1 modified human T cells results in an increased time to tumor progression and overall survival in a dose dependent manner when compared to mice treated with T cells transduced with an irrelevant artificial T cell receptor (Pz1). However, interpretation of this data is limited by the xenogeneic nature of the T cells and tumor cells to the SCID-Beige mouse, as well as the immune-compromised state of the host. Therefore, the overall objective of this proposal is to better define the activity of the 19z1 transduced T cells using a syngeneic immune competent mouse model. To this end, specific aim #1 of this proposal will establish a tumor model of syngeneic EL4(hCD19) tumor cells in an immune competent hCD19 transgenic mouse and establish whether 19z1+ murine T cells are able to eradicate disease in this model. To test the hypothesis that T helper cells play an important role in adoptive T cell therapy, aim #2 will define the role of transduced CD4+ T cells in the cytotoxic activity, homing and proliferation of transduced CD8+ T cells.
Specific aim #3 will test the hypothesis that secondary lymphoid tissues and bone marrow in cured mice will maintain a persistent population of transduced T cells. The functional status of these T cells will be analyzed by rechallenge of cured mice with EL4(hCD19) tumor cells. The data derived from these studies will be applied to the rational development of future clinical trials in human subjects with B cell malignancies.
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