PATHOLOGY & ONCOLOGY RESEARCHVol. 5 No. 1, 1999

 Article

Potential Use of T Cell Receptor Genes to Modify Hematopoietic Stem Cells for the Gene Therapy of Cancer

Timothy M CLAY, Mary C CUSTER, Paul J SPIESS, Michael I NISHIMURA

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, USA

 

The purpose of this review is to illustrate some of the technical and biological hurdles that need to be addressed when developing new gene therapy based clinical trials. Gene transfer approaches can be used to ''mark” cells to monitor their persistence in vivo in patients, to protect cells from toxic chemotherapeutic agents, correct a genetic defect within the target cell, or to confer a novel function on the target cell. Selection of the most suitable vector for gene transfer depends upon a number of factors such as the target cell itself and whether gene expression needs to be sustained or transient. The TCR gene transfer approach described here represents one innovative strategy being pursued as a potential therapy for metastatic melanoma. Tumor reactive T cells can be isolated from the tumor infiltrating lymphocytes (TIL) of melanoma patients. A retroviral vector has been constructed containing the T cell receptor (TCR) &agr; and &bgr; chain genes from a MART-1(27-35)-specific T cell clone (TIL 5). Jurkat cells transduced with this virus specifically release cytokine in response to MART-1(27-35) peptide pulsed T2 cells, showing that the virus can mediate expression of a functional TCR. HLA-A2 transgenic mice are being used to examine whether transduced bone marrow progenitor cells will differentiate in vivo into mature CD8+ T cells expressing the MART-1(27-35)-specific TCR. Expression of the human TCR &agr; and &bgr; chain genes has been detected by RT-PCR in the peripheral blood of HLA-A2 transgenic mice reconstituted with transduced mouse bone marrow. Expression of the TIL 5 TCR genes in the peripheral blood of these mice was maintained for greater than 40 weeks after bone marrow reconstitution. TIL 5 TCR gene expression was also maintained following transfer of bone marrow from mice previously reconstituted with transduced bone marrow to secondary mouse recipients, suggesting that a pluripotent progenitor or lymphocyte progenitor cell has been transduced. Pathology & Oncology Research, Vol 5, Nr 1, 3-15, 1999

Key words: adoptive immunotherapy; gene therapy; stem cell; T cell receptor; tumor antigen


Received: Dec 21, 1998; accepted: Jan 16, 1999
Correspondence: Timothy M CLAY, Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B04, 10 Center Drive Bethesda 20892, USA; Tel: (301) 402-4124, Fax: (301) 402-1788; E-mail: Tim_Clay@nih.gov.usa

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