Genetic immunotherapy for malignancy: murine modeling

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DESCRIPTION (provided by applicant): Adoptive immunotherapy has great promise as a fourth treatment modality for malignancy, but significant obstacles remain, including tumor specificity, maintenance of effector T cell function and optimal activation strategy. We have developed a system of primary T cell activation with anti-CD3 and anti-CD28 followed by retroviral transduction to generate T cells expressing genetically engineered, tumor-specific receptors. While preliminary experiments show therapeutic promise, the kinetics, function and IL-2 dependence of such cells in vivo has not been rigorously studied. The efficacy of gene-therapy modified primary T cells expressing a new, tumor-specific alpha/beta T cell receptor (TCR) in vivo remains to be demonstrated. Ovalbumin has been used as a surrogate tumor antigen in many systems. We propose to create a bicistronic retroviral expression vector encoding the ovalbumin-specific T cell receptor alpha and beta genes from the OT-1 T cell receptor transgenic mouse (OT-1 Tg). We will use Ly 5.1 congenic donors to compare gene-therapy modified T cells to OT-1 Tg T cells for kinetics, IL-2 dependence and antigen response after adoptive transfer. Using the murine lymphoma model cell line EL-4 and the murine leukemia model cell line C 1498, each transduced to express ovalbumin, we will test the therapeutic efficacy of gene-therapy modified T cells. These studies will provide data important for modeling future clinical trials of adoptive immunotherapy with genetically modified T cells to treat lymphoma and leukemia.