Efficient and nontoxic adenoviral purging method for autologous transplantation in breast cancer patients

Tumor cell contamination of clinical grafts is a major concern in autologous hematopoietic stem cell transplantation because these contaminating cells can contribute to relapse. In the present work, we use a suicide gene therapy approach that successfully accomplishes the two main goals of any purgi...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-09, Vol.62 (17), p.5013-5018
Main Authors: LILLO, Rosa, RAMIREZ, Manuel, VICARIO, José Luis, BUEREN, Juan Antonio, GARCIA-SANCHEZ, Félix, ALVAREZ, Angela, SANTOS, Silvia, GARCIA-CASTRO, Javier, FERNANDEZ DE VELASCO, Jaime, AVILES, Maria José, GOMEZ-PINEDA, Alfonso, DIEZ, José Luis, BALAS, Antonio
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Applied cell therapy and gene therapy
Biological and medical sciences
Bone Marrow Purging - methods
Breast Neoplasms - pathology
Breast Neoplasms - therapy
Cytosine Deaminase
Female
Flucytosine - pharmacokinetics
Genetic Therapy - methods
Gynecology. Andrology. Obstetrics
Hematopoietic Stem Cell Transplantation - methods
Humans
Male
Mammary gland diseases
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Nucleoside Deaminases - genetics
Nucleoside Deaminases - metabolism
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
Tumor Cells, Cultured
Tumors
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Summary:Tumor cell contamination of clinical grafts is a major concern in autologous hematopoietic stem cell transplantation because these contaminating cells can contribute to relapse. In the present work, we use a suicide gene therapy approach that successfully accomplishes the two main goals of any purging strategy: highly efficient elimination of contaminating tumor cells and preservation of the engraftment capability of the hematopoietic progenitor cells. Human CD34(+) cells spiked with breast cancer cells were infected with an adenoviral vector encoding the cytosine deaminase transgene (Ad-CMV-CD). In vitro, transduction with Ad-CMV-CD followed by exposure to 400 micro M 5-fluorocytosine resulted in complete elimination of clonogenic contaminating tumor cells without affecting the clonogenic potential of the human hematopoietic CD34(+) cells. Transplantation of nonobese diabetic/LtSz-scid/severe combined immunodeficient (NOD/SCID) mice with nonpurged contaminated grafts and purged contaminated grafts, allowed us to test the safety and efficacy of our procedure in two independent purging experiments. Hematopoietic engraftment kinetics as well as the quantity and quality of human engraftment were not affected by the purging therapy. Results showed a significant difference in survival between the nonpurged group (28%) and the purged group (100%; P = 0.012). Moreover, highly sensitive histological and molecular analyses confirmed the absence of tumor cells in the recipients of purged marrow. In contrast, metastatic tumors were detected in animals that received nonpurged grafts. We anticipate that this strategy will result in a safe and efficacious hematopoietic graft product for autologous transplantation for patients with multiple forms of epithelial cancers.
ISSN:0008-5472
1538-7445