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PubMed1996

CD34+ progenitor cell selection: clinical transplantation, tumor cell purging, gene therapy, ex vivo expansion, and cord blood processing.

A unique avidin-biotin immunoadsorption system (CellPro CEPRATE SC) has been developed for the rapid clinical scale purification of CD34+ cells from bone marrow, mobilized peripheral blood (PBSC), or cord blood. This system has been used to treat more than 2500 patients worldwide in a variety of clinical studies. In the autologous transplantation setting, selection for CD34+ cells results in significant reduction (2- > 5 logs) of contaminating tumor cells in the enriched fractions, as documented using sensitive immunocytochemistry staining techniques or quantitative PCR analyses. In the allogeneic bone marrow or PBSC transplant setting, using the CEPRATE SC system as a method for T cell depletion has shown a 3-log reduction in overall T cell content, with more rapid hematopoietic recovery after PBSC reinfusion as compared with bone marrow. CD34+ enrichment is required for efficient ex vivo expansion of progenitor cells as well as for gene therapy applications involving the genetic modification of stem cells.

Antigens, CD↗
PubMed2002

Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death.

Activation enhanced cell death (AECD) involves stimulating cells with growth or activation signals while concurrently blocking calcium influx. In this study, we have evaluated the effect of AECD on human breast cancer cells. MCF-7 or MDA-MB-231 cells treated with Ca2+ influx blockers econazole or ketotifen for 24 h underwent a dose-dependent, irreversible loss of viability, and clonogenicity. Two-hour treatment of these cells with higher concentrations of the drugs also resulted in loss of clonogenicity, but morphological indicators of cell death were apparent only after longer incubation. Loss of clonogenicity could be enhanced almost 10-fold by co-stimulation of the cells with the agonists EGF or bombesin. Econazole was also effective in inducing cell death in multi-drug resistant MCF-7adr cells. Human hemopoietic progenitor cell sensitivity to econazole or ketotifen was evaluated by colony assay. Under conditions resulting in 2.5-3 logs of breast cancer cell loss, 60-70% of hemopoietic progenitors could be recovered. We further evaluated the effect of econazole on breast cancer cells present in mobilized hemopoietic cells obtained from patients undergoing high dose chemotherapy with autologous stem cell support. In six of eight samples evaluated, cytokeratin-positive breast cancer cells could be detected by immunofluorescence microscopy and colony formation. Breast cancer colonies were reduced 60-500-fold or more after exposure to econazole while hemopoietic colonies were typically reduced only 2-fold. In all cases, addition of EGF as an activator either had no evaluable effect or enhanced breast cancer cell loss. We conclude that Ca2+ influx blockade with concurrent EGF stimulation is a promising approach for purging breast cancer cells from hemopoietic progenitor cell preparations.

Bone Marrow Purging↗
PubMed2002

Autologous stem cell transplantation and purging in adult acute lymphoblastic leukaemia.

The prognosis for adult acute lymphoblastic leukaemia (ALL) is poor. Only 20-30% of patients will be cured with conventional chemotherapy. Haematopoietic progenitor transplantation is thus an attractive option in these patients. Even if allogeneic transplantation allows a better control of the disease, autologous transplantation remains an important alternative for patients lacking a suitable donor or when allogeneic transplants imply excessive risk. Relapse is the main drawback of autologous transplants, but many strategies are being explored to overcome this problem. We focus here on transplant modality, the source of haematopoietic progenitors, and the best timing to apply the procedure. Also reviewed are the current situation and future strategies for improving results in this setting, such as ex vivo purging; immunotherapy and maintenance chemotherapy.

Adult↗
PubMed1997

Purging marrow or peripheral blood stem cells for autografting.

Myeloablative therapy followed by autologous bone marrow or peripheral blood stem cell rescue is an alternative therapeutic option for patients who are not candidates for allogeneic transplantation due to the lack of an appropriate HLA-matched donor or to advanced age. It allows therapy to be administered that is of comparable intensity to that used for allogeneic transplantation, and offers an alternative approach to achieving long-term disease-free survival. Although autologous transplantation obviates the risk of graft-versus-host disease, with its increased morbidity and mortality, it may also increase the rate of disease relapse due to the lack of an immune-mediated graft-versus-leukemia effect, as occurs in the allogeneic transplantation setting. The possibility that residual occult neoplastic cells, reinfused with the remission autografts following myeloablative therapy, can potentiate disease relapse has also been a concern in patients who undergo autologous bone marrow transplantation. This review discusses recent data concerning various strategies that are being used to "purge" autografts in patients undergoing autologous bone marrow transplantation in an effort to decrease the relapse rates and improve the disease-free and overall survival.

Antineoplastic Agents↗
PubMed1999

Bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia.

Treatment of low-grade lymphoma and chronic lymphocytic leukemia (CLL) is a challenge for hematologists. The long physical history and the indolent nature of these diseases do not support the choice of aggressive treatment. However, regardless of the initial sensitivity of these diseases to chemotherapy and radiotherapy, relapse is inevitable and, therefore, treatment choice especially for younger patients is a serious decision. Intensive therapy followed by transplantation with purged autologous bone marrow or peripheral blood progenitor cells has been shown to be efficient in low-grade lymphomas. However, long-term follow-up study has shown a continuous pattern of relapses, many of which are due to the reinfusion of malignant cells, as well as a risk for the development of myelodysplasia and acute myeloid leukemia. Allogeneic bone marrow transplantation (BMT) is an attractive, promising alternative approach that eliminates many of these risks. Treatment of CLL with classical chemotherapeutic agents, as well as biological response modifiers has not provided any significant improvement in the long-term outcome and remission duration. Addition of autologous BMT (ABMT) or allogeneic BMT as a consolidation therapy is under study and might be a step toward a potential cure of this disease.

Bone Marrow Transplantation↗
PubMed1987

Purging breast cancer cells in preparation for autologous bone marrow transplantation.

Mixtures of the T-47D human breast cancer cell line and normal human bone marrow cells were used for studying a new approach for purging epithelial tumor cells for autologous bone marrow transplantation (BMT) in breast cancer. Breast cancer cell line T-47D cells were shown to bind soybean agglutinin (SBA) in a specific fashion that could be blocked by D-galactose. Tumor cells were effectively purged by both SBA agglutination and depletion of cells bound to magnetic beads (0.7-5.0 micron) covalently linked to SBA. A depletion of 3-4 orders of magnitude of tumor cells was consistently accomplished by combining one step of agglutination followed by one cycle of SBA-magnetic bead depletion. Neither procedure affects stem cell recovery. We suggest that effective purging of breast cancer cells can be accomplished using SBA for autologous BMT in patients with advanced breast cancer.

Agglutination↗
PubMed2004

B-cell purging in autologous stem-cell transplantation for non-Hodgkin lymphoma.

Autologous stem-cell transplantation is a common therapy for B-cell non-Hodgkin lymphoma. However, a concern with the procedure is the potential of malignant cells to reinfuse with the stem-cell graft. Thus attempts have been made to purge, or eliminate, malignant cells from the graft. The oldest, and most well studied, method for prevention of reinfusion is in vitro use of antibodies against B cells that bind or lyse malignant B cells and healthy cells, while leaving T cells and stem cells to be reinfused. In the past 5 years, investigators have used rituximab, an antibody against CD20, to purge malignant cells in vivo without any manipulation in vitro. Both conventional and new techniques have shown promise, but their exact role remains to be defined. We analysed data on the purging of B cells by use of antibodies in the setting of autologous transplantation, with emphasis on the emerging technique of in vivo purging.

Antibodies, Monoclonal↗
PubMed1999

[Ex vivo and in vivo purging for PBSCT].

Relapse due to either residual host disease or reinfused tumor cells remains the principal cause of treatment failure after autologous stem cell transplantation. It is very attractive to remove contaminated tumor cells from autologous grafts prior to transplant and many purging techniques including hyperthermia we developed, have been reported on this subject. However, there are only limited data suggesting that purging autografts have any favorable effect on relapses or disease-free survival. Drug-treated purging and CD34 positive cell selections that remove substantial numbers of T cells or destroy stem cells may have adverse effects such as delayed hematopoietic or T cell recovery. Therefore, there is a critical need for large, well-designed trials to re-evaluate ex vivo and in vivo purging effects on relapses and disease-free survival after autologous stem cell transplantation.

Animals↗
PubMed1990

[Evaluation of a modified immunomagnetic procedure for the purging of neuroblastoma cells from bone marrow].

The immunomagnetic depletion method for removing tumor cells from bone marrow, previously refined using a Burkitt lymphoma model, was tested with neuroblastoma cells. The efficiency of depletion was quantified by immunofluorescence with a detection limit of 3.3 log of cell depletion corresponding to the elimination of 99.84% of an initial tumor cell content of 10%. A panel of five monoclonal antibodies (UJ13A; UJ127.11; UJ181.4; alpha-Thy1; H11) purged 2.8 log of SKNBE and LAN-1 cells, while two of these antibodies as single agents allowed only for a 1.7 log (UJ13A) and a 1.7 to 2.0 log (alpha-Thy1) depletion. This underlines the advantage of an antibody panel for neuroblastoma purging. The new antibody S-L 11.14, an IgG2a against small cell lung cancer which recognizes 90% of neuroblastoma cells purged 2.8 log.

Antibodies, Monoclonal↗
PubMed1998

Should we purge?

Relapse due to either residual host disease or reinfused tumor cells remains the principal cause of treatment failure after autologous stem cell transplantation. Although it is intuitively attractive to remove putative tumor cells from autologous grafts prior to transplant and more than 1000 articles have been written on the subject, there are only limited data suggesting that purging autografts has any favorable effect on relapses or disease-free survival. Certain purging techniques that remove substantial numbers of T cells or destroy progenitor cells may have adverse effects such as delayed hematopoietic or T cell reconstitution. There is a critical need for large, well-designed trials that specifically address the value of a particular purging technique on relapses and disease-free survival after autologous stem cell transplant.

Antigens, CD34↗
PubMed1990

Autologous bone marrow transplantation for B cell malignancies after in vitro purging with floating immunobeads.

We report here 16 autologous bone marrow transplantations (ABMT) for poor prognosis B or pre-B malignancies (16 acute lymphoblastic leukemias (ALL), three Burkitt lymphomas, one multiple myeloma) in 11 adults and five children where in vitro purging was accomplished by means of floating immunobeads. This method was developed to avoid non-specific killing by complement or toxin or batch-to-batch variability and provides a 3 log reduction of tumor in a model of B lymphoid malignancies. Low density bone marrow mononuclear cells were incubated for 30 min at 4 degrees C with anti CD10 (ALB2 Immunotech) and/or anti CD19 (Bg4) monoclonal antibodies (MoAb) and then mixed with low density polypropylene beads precoated with a rat antimouse MoAb. After 1 h at 4 degrees C the beads with target cells were decanted; the depleted marrow was collected through a microfilter and cryoperserved. After immunodepletion the recovery of nucleated cells was 75% with a median of 0.75 x 10(8) cells/kg (range 0.3-3.6) and the recovery of hematopoietic progenitors was 83% with a median of 2.9 x 10(4) CFU-GM/kg. The conditioning regimen consisted of busulfan 16 mg/kg and melphalan 140 mg/m2 for three patients, fractionated total body irradiation (TBI) following melphalan 140 mg/m2 for nine patients, TBI and cyclophosphamide 120 mg/m2 for two patients and TBI associated with melphalan and cyclophosphamide for two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Standardization of monoclonal antibodies for use in autologous bone marrow transplantation for common acute lymphoblastic leukemia.

Two monoclonal antibodies suitable for leukemia cell purging of remission bone marrow from patients with common acute lymphoblastic leukemia (common-ALL) are described. WM-21, reacting with the gp 100 common-ALL associated antigen (CALLA), and FMC-8, reactive with a p24 surface antigen, both bind to the majority of leukemic blast cells from cases of common ALL, and promote complement-mediated lysis of CALLA+ leukemias and cell lines. After initial dye exclusion studies to standardize antibody and rabbit complement concentrations and incubation times, an in vitro plating assay using CALLA+ p24+ cell lines was used to investigate the lytic ability of monoclonal antibody treatment. Incubation with WM-21, FMC-8, and complement produced up to 5 logs inhibition of growth in this system. Under similar conditions, no inhibition of in vitro growth of normal bone marrow myeloid progenitor cells was seen. These antibodies therefore appear to be useful therapeutic reagents for removing residual common ALL blast cells from bone marrow prior to autologous marrow transplantation.

Antibodies, Monoclonal↗
PubMed2001

Purging of myeloma cells using all-trans retinoic acid in a mouse model.

OBJECTIVE: The 5T33 murine model of multiple myeloma was used to investigate the potential of all-trans retinoic acid (ATRA) to purge clonogenic myeloma cells from autologous hemopoietic stem-cell harvests by differentiating immature 5T33 cells into terminal-stage plasma cells with limited repopulation capacity. MATERIALS AND METHODS: 5T33 cells were treated with 10 microM ATRA and the effect on cell clonogenicity was determined by measuring the time to paraprotein detection in C57Bl/KaLwRij mice compared to control animals. Cell differentiation and apoptosis following ATRA treatment were investigated using flow cytometry and caspase-3 assay. Treatment with ATRA resulted in a 33% reduction in the in vitro cloning efficiency of 5T33 cells. Reduced in vitro clonogenicity of 5T33 cells following ATRA treatment was supported by a 16-49% increase in the time taken for C57Bl/KaLwRij mice to develop paraprotein following injection of 5T33 cells pretreated with ATRA for 8 days. Although ATRA was shown not to alter the in vitro growth characteristics of 5T33 cells, significant inhibition of apoptosis was observed. RESULTS: Treatment with ATRA also resulted in an increase in the proportion of 5T33 cells expressing the CD54 adhesion molecule, which is known to be highly expressed on mature myeloma cells. CONCLUSION: The ability of ATRA to decrease the clonogenicity of 5T33 cells in vitro and increase the time to disease development in vivo suggests that this drug may be useful for purging autologous stem cell harvests in the clinical setting.

Animals↗
PubMed2002

High-dose therapy for indolent lymphoma.

Stem-cell transplantation (SCT) has become the treatment of choice for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). However, the role of SCT in the management of patients with indolent NHL remains controversial. Indolent follicular lymphomas are diseases which are generally incurable with conventional therapy. Although patients can survive for prolonged periods, the median duration of first remission is approximately 3 years, and subsequent remissions are progressively shorter with time. Emerging evidence suggests that high-dose chemotherapy with SCT leads to prolonged disease-free and overall survival in a subset of patients with indolent NHL. However, there is increasing concern regarding the toxicity of SCT, especially the long-term risk of developing myelodysplastic syndrome. It is still unclear as to when this approach should be used. Poorer outcomes have been obtained in heavily pretreated patients but encouraging results are being reported for patients undergoing SCT early during the course of their disease. Investigators are now focusing on how to improve SCT efficacy in order to eradicate minimal residual disease. Many ongoing studies are especially exploring the impact of stem-cell purging and novel ablative regimens combined with allogeneic transplantation.

Antineoplastic Agents↗
PubMed1993

Interferon gamma is effective for BM purging in a patient with CML.

We report a case of Ph-positive CML where the BM was incubated for 24 h with 10(3) IU/ml IFN gamma and then cultured in liquid media for 4 weeks. After 24 h incubation, there was no differential sensitivity of CML CFU-GM to IFN gamma compared with untreated BM. Subsequent long-term culture (LTC) of the IFN gamma treated CML BM, however, demonstrated a 75% inhibition of production of CFU-GM from the second week onwards. Using PCR, we were able to demonstrate two types of BCR-ABL transcript in the diagnostic BM. After 4 weeks of LTC, the J(bcr b3/ABL II) RNA transcript persisted in the untreated BM, whereas neither BCR/ABL RNA transcripts were detected in the culture established with IFN gamma-treated CML BM. This study has two points of interest with the demonstration of (1) a possible antileukaemic effect of IFN gamma on the progenitors generated in the LTC system, and (2) the use of highly sensitive PCR technology to evaluate the effectiveness of IFN gamma to purge CML BM of Ph-positive cells.

Bone Marrow↗
PubMed1987

Experimental studies on the role of alkyl lysophospholipids in autologous bone marrow transplantation.

The selective cytocidal effect of alkyl lysophospholipids against neoplastic cells while sparing normal cells make these ideal candidates for purging leukemic cells from bone marrows obtained during remission. To test the feasibility of such an approach, a murine model and an in vitro human cell model were developed. In the murine system a mixture of normal bone marrow cells and WEHI IIIB myelomonocytic leukemic cells was incubated with varying doses of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-Me) for 24 hr before being injected into tail veins of lethally irradiated Balb/c mice. At doses of 20 and 100 micrograms/ml, long-term survivors were noted. The additional steps of freezing and thawing following incubation resulted in significantly longer survival with doses of 10 to 50 micrograms/ml, but were toxic to marrow stem cells at 100 micrograms/ml. In the in vitro model, normal marrow progenitor cells and leukemic cells (the promyelocytic cell line HL60) were exposed to varying concentrations of ET-Me for 1 and 4 hr alone or mixed, and clonogenicity was assayed by colony formation in semisolid medium during 7-14 days' incubation. At doses up to 100 micrograms/ml exposed for 4 hr normal progenitor cells were spared and HL60 colonies eliminated. Other phospholipids analogues were less effective in eliminating leukemic cells, but spared normal progenitor cells. A survey of fresh leukemic cells found varying degrees of sensitivity to ET-Me, indicating the need for testing a variety of compounds. These studies clearly indicated the potential usefulness of alkyl lysophospholipid compounds in selectively purging leukemic cells from remission marrows for autologous bone marrow transplantation.

Animals↗