Future Paradigm for Autologous Bone Marrow Transplantation: Tumor Purging andEx VivoProduction of Normal Stem and Progenitor Cells

Abstract

A major concern in autologous bone marrow transplantation (ABMT) is the possible contamination of the graft with tumor cells. Transplantation of malignant cells, along with normal hematopoietic stem and progenitor cells, may contribute to relapse of disease. Therefore, a growing strategy is to subject autologous marrow to some type of purging procedure to eliminate tumor cells selectively. Transplantation of purged marrow, however, often results in a delayed engraftment associated with (specific or nonspecific) loss of normal stem and progenitor cells during manipulations related to the purging process. A new and burgeoning field in the area of clinical bone marrow transplantation is the ex vivo production of stem and progenitor cells. Several advantages accrue to this strategy. First, this technology makes it possible to expand the stem and progenitor cell population of a small volume of bone marrow or mobilized peripheral blood (MPB), thus lessening the initial tumor burden to be purged. Secondly, ex vivo marrow or MPB expansion may overcome the significant problem of delayed engraftment by rebuilding the numbers of normal stem and progenitor cells necessary for both early and durable engraftment. To accomplish these and other objectives, an automated and closed, clinical-scale bioreactor system, based on continuous perfusion technology, is being developed and will soon enter clinical trials.

The Removal of Human Breast Cancer Cells from Hematopoietic CD34+Stem Cells by Dielectrophoretic Field-Flow-Fractionation

“…A U TOLO GO US S TEM C ELL TR AN SPL AN TATION for reconstituting a cancer patient's hematopoietic system following dose-intensive chemotherapy and radiation therapy can be confounded by metastatic tumor cell contamination of the graft, which may cause disease recurrence (1)(2)(3)(4)(5). Currently, tumor cells are purged from autografts by pharmacologic, immunologic, or biophysical methods (6) or by positive selection of hematopoietic stem cells (HSC) with CD34 antibody-sensitized magnetic beads (7,8).…”

Purging of human breast cancer cells from stem cell products with an adenovirus containing p53

“…43 The selection of CD34 ϩ hematopoietic progenitor cells also has been used to reduce TC reinfusion, although this strategy may be slightly less effective (1-2.5 logs). However, purging using cytotoxic drugs often leads to delayed engraftment, 44 and purging by CD34 ϩ cell selection may inhibit immune recovery. 45 Furthermore, the loss of p53 function is known to be associated with TC resistance to antitumor therapy.…”

Adenovirus p53 Purging for Human Breast Cancer Stem Cell Products

“…These observations suggest that TC removal (purging) from stem cell products could significantly affect clinical outcome. The use of monoclonal antibodies against membrane antigens with cytotoxic drugs or toxins, phototherapy, biological response modifiers, or cytotoxic drugs can reduce tumor contamination by 1–3 logs but often with delayed engraftment [30]. The selection of CD34+ hematopoietic progenitor cells also has been used to reduce TC reinfusion, with the results slightly less effective (1–2.5 logs).…”