Adoptive T cell therapy (ACT) has shown potential in the treatment of tumors and viral infections. Recent approaches in ACT include genetically engineered T cells which carry new antigen specificity achieved by T cell receptor (TCR) gene transfer. However, the first clinical trials using TCR gene-modified T cells to treat melanomas showed a limited success. TCR gene transfer into hematopoietic stem cells (HSC) is another option to endow T cells with new antigen specificities. This approach has some advantages. However, engineering of HSC bears the risk of vector-induced insertional mutagenesis which could lead to an uncontrolled clonal proliferation and to lymphoma development.
We will analyze benefit versus risk using TCR gene-modified HSC (TCR-retrogenic T cells) for ACT. We will compare the therapeutic efficacy of TCR-retrogenic, TCR-transduced, and TCR-transgenic T cells in virus disease and tumor models. We will analyze safety issues with regard to the transduction of HSC by means of ?-retroviral vectors. We generated mice bearing one TCR-specific T cell subpopulation where the TCR expression is regulated by retroviral promoters while in the second subpopulation the TCR expression is driven by cellular promoters. Both T cell subpopulations differ in their congenic markers and allow to distinguish which cell is the source for tumor development if this should happen after chronic antigen stimulation of the cells.

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