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Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling

Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Richard A. Morgan, Surgery Branch, National Cancer Institute, Room 3W5940, Building 10, 10 Center Drive, MSC 1201, Bethesda, MD 20892-1201. Phone: 301-594-9629; Fax: 301-435-5167; E-mail: rmorgan{at}mail.nih.gov.

Adoptive cell transfer (ACT) of tumor-reactive lymphocytes has been shown to be an effective treatment for cancer patients. Studies in murine models of ACT indicated that antitumor efficacy of adoptively transferred T cells is dependent on the differentiation status of the cells, with lymphocyte differentiation inversely correlated with in vivo antitumor effectiveness. T-cell in vitro development technologies provide a new opportunity to generate naive T cells for the purpose of ACT. In this study, we genetically modified human umbilical cord blood–derived hematopoietic stem cells (HSCs) to express tumor antigen-specific T-cell receptor (TCR) genes and generated T lymphocytes by coculture with a murine cell line expressing Notch-1 ligand, Delta-like-1 (OP9-DL1). Input HSCs were differentiated into T cells as evidenced by the expression of T-cell markers, such as CD7, CD1a, CD4, CD8, and CD3, and by detection of TCR excision circles. We found that such in vitro differentiated T cells expressed the TCR and showed HLA-A2–restricted, specific recognition and killing of tumor antigen peptide–pulsed antigen-presenting cells but manifested additional natural killer cell–like killing of tumor cell lines. The genetic manipulation of HSCs has broad implications for ACT of cancer. [Cancer Res 2007;67(6):2425–9]

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