Attractive target cells in gene transfer approaches to cancer treatment are pluripotent hematopoietic stem cells (HSCs) because of their high proliferative potential, self renewal and the wide systemic distribution of their progeny. A retroviral-mediated approach to gene transfer into HSCs is currently favored because the transduced gene is permanently integrated into the genome of the target cell resulting in the long-term stable expression of the gene product. Unfortunately, this approach requires that the target cell be in cycle and thus retroviral transduction of normally quiescent HSCs generally occurs at low efficiency. In previous work we have demonstrated that reinfused genetically marked long term bone marrow culture cells contribute significantly to long term hematopoiesis in a canine model. If also true in humans, such experiments suggest that bone marrow cells could be removed, transduced with a retroviral vector carrying a gene of known therapeutic effect and reinfused into the autologous recipient with minimal toxicity. The demonstration of successful long term gene transfer in humans would be an important prelude to therapeutic trials using genetically modified cells. To proceed in this new direction, important biological questions about the safety and feasibility of treatment with gene marked cells must first be addressed. We have therefore obtained local institutional review board and Canadian Health Protection Branch approval for a phase I clinical trial which it is hoped will extend our understanding of the behavior of gene marked hematopoietic progenitor cells in vivo. In this trial gene marked autologous marrow cells will be reinfused into volunteer patients undergoing myeloablative treatment for multiple myeloma. In this paper we describe the background to our ongoing trial and provide a trial outline.
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