Stem Cells, Vol. 18, No. 2, 87-92,
March 2000
© 2000 AlphaMed Press
Clinical Applications of CD34+ Peripheral Blood Progenitor Cells (PBPC)
Wichard Vogel,
Stefan Scheding,
Lothar Kanz,
Wolfram Brugger
Department of Hematology, Oncology, Rheumatology and Immunology, Medical Center II, Eberhard-Karls-University, Tübingen, Germany
Key Words. CD34+ • Selection technologies • Autologous • Allogeneic • Transplantation
Wolfram Brugger, M.D., Department of Medicine, Otfried-Müller-Str. 10,72076 Tübingen, Germany. Telephone: 49-7071-2983698; Fax: 49-7071-295591; e-mail:wolfram.brugger{at}med.uni-tuebingen.de
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Abstract
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Recently, a number of devices have been developed for the positive selection of CD34+ peripheral blood progenitor cells (PBPC) for clinical use in autologous or allogeneic transplantation. The rationale for CD34+ selection is based on clinical studies showing a two- to five-log reduction of contaminating tumor cells in patients with breast cancer, multiple myeloma and low-grade lymphoma. In addition, a three- to five-log reduction of T cells can be obtained by CD34+ selection in both autologous grafts for patients with autoimmune disease resistant to conventional therapy and allogeneic grafts to reduce the incidence and severity of acute graft-versus-host disease.
Transplantation of positively selected autologous CD34+ PBPC results in a rapid and stable neutrophil and platelet engraftment in patients who received an infused dose of at least 2.0 x 106 CD34+ cells/kg. Results from randomized trials suggest that time to engraftment is not different compared to unmanipulated PBPC autografts. However, close monitoring for infectious complications (e.g., cytomegalovirus disease) is required. Allogeneic CD34+ PBPC have also been successfully transplanted and, using novel technologies, megadoses of purified CD34+ PBPC can be obtained and used to overcome histocompatibility differences betweeen allogeneic donor and patient resulting in stable engraftment, even in a haploidentical setting. Additional randomized phase III trials are required to determine whether tumor cell purging or lymphocyte depletion by CD34+ cell selection will have a significant impact on progression-free and overall survival in both autologous and allogeneic transplantation.
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CD34+ Cell Selection Technologies
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The first computer-controlled system for clinical selection of CD34+ cells from bone marrow or peripheral blood was the CEPRATE Stem Cell Concentrator system (CellPro Inc; Bothell, WA). In this system, peripheral blood progenitor cells (PBPC) incubated with biotinylated antibody to CD34 are perfused through a disposable column packed with avidin-coated polyacrylamide beads. CD34+ cells bind to the beads via the biotinylated antibody, while CD34– cells flow through the column without binding. Bound CD34+ cells are released by a magnetic stirring bar [1, 2]. This system has been used to treat a large number of patients in a variety of clinical studies [3-5], however, the CellPro system is no longer available.
The first clinically used magnetic CD34+ selection system was the Isolex Magnetic Cell Separation System (Baxter Health Corporation; Irvine, CA). Immunomagnetic beads are added to anti-CD34-sensitized PBPC. The beads/rosettes are separated from the unbound cells using the magnet of the Isolex System. Series of washes are performed to remove nontarget cells [6]. Simultaneous positive/negative selection procedures using the Isolex system can result in tumor cell reduction of four to six log [7]. Numerous small phase I/II clinical studies have been performed with CD34+-selected grafts generated by this system [8-10].
The most recent development was the AmCell Selection Device which is a fully automated large-scale isolation system based on a previously developed research scale magnetic-activated cell separation system ([MACS]; Miltenyi Biotech GmbH; Bergisch Gladbach, Germany) for the selection of CD34+ cells both from PBPC or bone marrow. Analyses of the selected products demonstrated a four- to five-log reduction of T-cell subsets and, generally, a CD34+ cell purity of greater than 90% [11]. Clinical studies using the AmCell device have been recently started in Europe (see below).
Another possibility for the generation of highly purified CD34+ PBPC for clinical transplantation is high speed fluorescence-activated cell sorting [12]. However, few clinical data are available because of the difficult technical procedure (time-consuming, problems with sterility and viability of PBPC) and high costs. Therefore, this technology has not become a standard application in clinical transplantation.
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Autologous Transplantation Of CD34+-Selected Cells
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The leukapheresis products of patients with breast cancer, multiple myeloma, and low-grade lymphoma contain significant numbers of malignant cells [13-15]. Results of studies performed in the early 1990s suggested that graft-contaminating tumor cells can have an impact on clinical outcome. Bone marrow cells of patients with leukemia and neuroblastoma were marked using retroviral-mediated gene transfer of a neomycin-resistant gene, and relapsed patients had evidence of the marker gene in the malignant cells, suggesting that these cells might contribute to disease recurrence [16]. Moreover, transplantation of bone marrow containing tumor cells detected by polymerase chain reaction (PCR) was associated with a significantly higher relapse rate in follicular non-Hodgkin's lymphoma patients than transplantation of PCR-negative grafts [17].
In breast cancer, disease-free survival can potentially be prolonged in those patients whose bone marrow or PBPC harvests were successfully purged in vitro by CD34+ cell selection, versus those patients whose harvests still contained epithelial tumor cells after CD34+ cell selection [18]. However, a clinical benefit of CD34+ cell selection in breast cancer or any other disease has not yet convincingly been demonstrated. Therefore, there is no reason for CD34+ cell selection for these patients except for clinical studies that are currently being performed in myeloma, low-grade non-Hodgkin's lymphoma, or breast cancer.
Finally, since the efficacy of the CD34+ cell selection systems has improved significantly and most of the early clinical studies have been performed with the CellPro system, it might be possible to further reduce the number of contaminating tumor cells (e.g., with the MACS system) which ultimately might positively affect clinical outcome.
PBPC collections are contaminated with tumor cells less frequently than corresponding bone marrow harvests. In clinical practice, the risk of tumor cell contamination is reduced by in vivo purging with cytoreductive chemotherapy before progenitor cell harvest. Studies of patients with high-risk and metastatic breast cancer showed that the incidence of tumor cell contamination of leukapheresis products ranged from 4%-20%, with few patients having had extremely high levels of circulating tumor cells [19, 20]. Whether breast cancer patients with such high levels of tumor cell contamination in leukapheresis products might benefit from CD34+ selection is unknown at the present time. This high level of contaminating tumor cells might rather be an indicator of poor prognosis patients with high tumor burden. Therefore, not surprisingly, the progression-free survival for high-risk breast cancer patients was identical on the unselected and the selected arms in a prospective randomized study using buffy coat versus CD34+-selected autologous bone marrow support [21].
PBPC transplantation is frequently used in multiple myeloma patients since high-dose chemotherapy has been shown to improve the overall survival [22, 23]. In this disease, positive selection of CD34+ PBPC markedly reduced the contamination of myeloma cells from apheresis products (up to three log); however, it did not abrogate myeloma cell contamination as measured by PCR in most of the apheresis products using the CellPro system [24-26]. Similar to the situation in breast cancer patients, there was no apparent clinical benefit of CD34+ cell selection in myeloma patients in clinical studies with short follow-up in terms of disease-free and overall survival (Table 1
).
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Table 1. Comparative studies of autologous transplantation with CD34+-selected versus unselected hematopoietic progenitor cells
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In addition to tumor cell reduction by "classical" purging with monoclonal antibodies and complement, a reduction of contaminating tumor cells has also been successfully performed upon positive selection of CD34+ cells in follicular low-grade lymphoma and chronic lymphocytic leukemia patients. It has been shown that this procedure is clinically feasible; however, similar to the situation in multiple myeloma patients, the CD34+ cell selection per se does not achieve completely tumor cell-free autografts, even after additional negative depletion with anti-CD19/20/23/37-labeled immunomagnetic beads; this method adds a two-log reduction of tumor cells but the grafts still remain PCR-positive [27, 28].
Based on these results, further therapeutic approaches like immunotherapeutic strategies (e.g., anti-CD20 antibody therapy for CD20+ low-grade follicular lymphoma and/or vaccination strategies) for the elimination of residual tumor cells as a potentially curative treatment option are required [29-31].
We are currently performing a clinical transplantation study using highly enriched CD34+ cells (CliniMACS, AmCell) after TBI/cyclophosphamide conditioning followed by anti-CD20-antibody (Rituximab) treatment [32] in newly diagnosed t(14;18)+ follicular lymphoma and t(11;14)+ mantle cell lymphoma (Fig. 1). The AmCell technology used in this ongoing study resulted in a median 97.5% pure CD34+ cell fraction (range 86.4-99.5) (Fig. 2), and based upon PCR results, 38% of the positively selected products were t(14;18)–. Therefore, it is reasonable to treat such patients after transplantation with CD20-antibody to eliminate minimal residual disease in vivo, and in fact, conversion of PCR positivity to negativity can be achieved by this approach (unpublished observation).
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Figure 1. Study of anti-CD20 Rituximab treatment after high-dose therapy and CD34+ blood stem cell transplantation for newly diagnosed follicular and mantle cell lymphoma.
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Figure 2. CD34+ cell selection using the CliniMACS device. Flow-cytometric analysis of CD34+ and CD3+ (A = leukapheresis product, B = CD34+-selected product).
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Another potential application of purified CD34+ cells after high-dose chemotherapy has recently emerged for the treatment of autoimmune disease. Long-term control of autoimmune disease has been demonstrated in some survivors of allogeneic transplantation for malignancy who incidentally had preexisting autoimmune disease. Autologous transplantation strategies use intensive conditioning regimens incorporating cyclophosphamide with or without TBI [33-35] and highly purified CD34+ PBPC grafts which contain only a few lymphocytes (<1 x 104/kg body weight). Importantly, close monitoring for adverse effects of intensive immunosuppression is required in these patients [36].
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Allogeneic Transplantation Of CD34+-Selected Cells
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Allogeneic bone marrow transplantation is generally regarded as the treatment of choice for most hematological malignancies. However, when matched unrelated donors are used, there is a significant risk of graft failure and of severe graft-versus-host disease (GVHD) [37, 38]. Therefore, depletion of T cells from the graft might be important and, in fact, it has been shown that T-cell depletion can reduce the risk of grade III/IV acute GVHD [39, 40].
Positively selected peripheral blood CD34+ cells also result in a reduced incidence of severe acute GVH in HLA-matched sibling donors [41-43] when compared to unmanipulated bone marrow or PBPC allografts. However, up to now, no randomized trials are available.
During the first six months after allogeneic transplantation with CD34+-selected PBPC, the number of total CD4+, CD4+CD45RA+, and TCR
/
+ cells is significantly lower when compared to unmanipulated allografts [44]. This low number of helper T cells might contribute to infectious complications as well as a potentially increased rate of relapses of the underlying hematological disease following CD34+-selected transplantation. In order to potentially decrease both the infectious complications as well as the risk of relapse, late add-backs of T cells as donor lymphocyte infusions might be required. The optimal dose and time of application of donor T cells following transplantation with allogeneic CD34+-selected PBPC, however, remain to be determined.
Among patients who can benefit from allogeneic transplantation, only 25%-30% have an HLA-identical sibling donor. With the recent development of unrelated donor registries, a further 20%-30% will find a suitable donor. In contrast, about 90% of all patients have an HLA haploidentical donor in their family. These family members could also be used as alternative stem cell donors. This is the major reason to develop and investigate the haploidentical transplantation using highly purified CD34+ cells for allogeneic PBPC transplantation [45, 46]. Megadose CD34+ cell grafts and a stringent T-cell depletion can be obtained with modern CD34+-selection technologies such as the MACS device, particularly for pediatric patients, as shown recently by Handgretinger et al. The average number of transplanted CD34+ cells was 14.2 x 106/kg (range 5.4-39 x 106/kg), and the average number of infused T cells was only 1.4 x 104/kg in a recent study of megadoses of haploidentical CD34+ cells. This strategy indeed resulted only in a minimal rate of GVHD [47, 48]. In adults, similar studies with mismatched or megadoses of haploidentical CD34+ cells have been performed [49].
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Future Prospects
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The ability to select CD34+ cells from mobilized peripheral blood makes it feasible to expand these purified cells in cytokine-supported cultures for clinical use. Aims for the ex vivo expansion of CD34+ PBPC are the generation of hematopoietic progenitor and stem cells, the generation of more mature myeloid and megakaryocytic post-progenitor cells and the induction of professional antigen-presenting, i.e., dendritic cells [50-52]. The transplantation procedure following high-dose chemotherapy might include the combined transplantation of the CD34+ PBPC for long-term engraftment, as well as the transplantation of ex vivo-generated neutrophil and megakaryocytic precursors and post-progenitor cells in order to potentially shorten hematological recovery [53, 54]. Whether the most primitive stem cells can actually be expanded ex vivo is still a matter of debate [55]. Finally, the expansion of primitive hematopoietic and mesenchymal progenitor/stem cells could not only be important in autologous or allogeneic transplantation, but also in gene therapy.
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accepted for publication February 8, 2000.
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Abstract
CD34+ Cell Selection...
