Peripheral Blood Stem Cells: In Vivo Biology and Therapeutic Potential zyx Stefan Scheding, Wolfram Bruggel; Roland Mertelsmann, Lothar Kanz zy Division of Hematology/Oncology, Department of Internal Medicine, Freibnrg University Medical Center, Freiburg, Germany Keywords. Peripheral blood stem cells PBSC Hematopoietic stem cells zyxw - High-dose chemotherapy Autologous PBSC transplantation PBSC recruitment Ex vivo expansion CD34 PBSC purification Abstract. Peripheral blood stem cells (PBSC) have been studied for their use after high-dose chemotherapy. The combination of a standard-dose chemotherapy [VIP: VP16 (etoposide), ifosfamide, cisplatin] in combination with hematopoietic growth fac- tors was shown to provide effective anti-can- cer activity as well as to enable sufficient stem cell mobilization for clinical use. Different growth factor regimens [granulo- cyte-colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, inter- leukin (IL)-3/GM-CSF] resulted in a differ- ential induction of high levels of circulating PBSC after VIP chemotherapy, with the sequential combination of IL-3 and GM-CSF inducing maximal numbers of CD34' cells as well as clonogenic progenitors. Our studies revealed a correlation between prior treat- ment and PBSC recruitment: the highest numbers of PBSC were mobilized in untreat- ed patients whereas stem cell harvest was considerably impeded in heavily pretreated patients. Phase UII trials demonstrated that transplantation of PBSC collected after VIP plus growth factor mobilization was safe, and engraftment was rapid and sustained. However, PBSC mobilization carried the risk of concomitant tumor cell recruitment in patients with detectable levels of tumor cells prior to therapy and in 21 % of patients without circulating tumor cells. Positive selection of CD34' cells by immunoadsorp- tion that leads to an approximately three-log depletion of contaminating tumor cells therefore was investigated with regard to feasibility and capability as a source for PBSC transplantation. Twenty-one patients with advanced malignancies received autolo- gous CD34' cell transplantation after high- dose chemotherapy. Hematological recovery was as rapid as recorded for unseparated PBSC preparations, indicating that CD34' cells can be safely used for autologous PBSC transplantation. Finally, combinations of hematopoietic growth factors were tested for their ability to expand hematopoietic prog- enitors in liquid culture. A five-factor combi- nation consisting of stem cell factor, erythro- poietin, IL-lp, IL-3 and IL-6 zyx was found to amplify progenitor cells optimally thereby providing the possibility of gaining large numbers of committed progenitor cells start- ing from only a few CD34' cells. Introduction High-dose chemotherapy is potentially curative in those chemosensitive tumors that are char- acterized by a relationship between dose intensity and tumor response. The rationale for such a high-dose chemotherapy approach is based on the fact that the relative dose intensity received is probably a major factor determining the outcome of chemotherapy [l]. However, dose intensification is inevitably linked to an aggravation of therapy-induced side-effects, with hematological toxicity often being the limiting factor. One way to overcome this dose- limiting hematotoxicity is to make use of peripheral blood stem cells (PBSC), which have been used increasingly as an alternative to bone marrow transplantation for autografting zy Polyfunctionality zyxwvutsr of Hemopoietic Regulators: The MetcalfFoium. STEM CELLS 1994;12(~~ppI1):203-211 Copyright zyxwvutsr 0 1994 by AlphaMed Press. All rights of reproduction in any form reserved. 203