CD34 selection for purging in multiple myeloma and analysis of CD34<sup>+</sup>b cell precursors

Früehauf, Stefan; Haas, Rainer; Hünstein, W.; Zeller, W. Jens

doi:10.1002/stem.5530120116

Cited by 33 publications

(12 citation statements)

References 23 publications

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“…[3][4][5] Positive selection for the CD34 ϩ antigen is currently the most frequently used purging strategy, achieving a 3-4 log tumor cell depletion in CD34 Ϫ malignancies. 6,7 Because residual tumor cells were detected after purging, 8 -10 alternative strategies including gene therapeutic approaches are being developed; viral vectors, for instance, can be used as vehicle to transport suicide genes into tumor cells. Retrovirus-based vectors are able to infect both HSCs 11,12 and tumor cells at a high frequency 13,14 and are therefore not suited for transduction of a whole stem cell graft with the aim of tumor cell purging.…”

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confidence: 99%

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

et al. 2000

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The use of autologous hematopoietic stem cell (HSC) grafts after high-dose chemotherapy protocols may be hampered by contamination of the grafts with tumor cells. Because epithelial cells seem to be the natural hosts of adeno-associated virus 2 (AAV-2), we speculated that epithelial tumor cells in HSC grafts might be selective targets for AAV-2-based vectors. To test this hypothesis, the breast cancer cell lines T47D and MCF-7 were infected with a recombinant AAV-2 vector expressing the green fluorescent protein (GFP) gene; in addition, human CD34 ϩ mobilized peripheral progenitor cells were infected with the same vector. At a multiplicity of infection of 100, only 1.39% Ϯ 0.51% CD34 ϩ cells expressed the GFP gene whereas, 36.06% Ϯ 6.53% of the infected T47D cells and 41.52% Ϯ 3.16% of the infected MCF-7 cells expressed the transduced GFP gene. After further optimizing the transduction procedure by using higher multiplicities of infection (100 -500) and preincubation of samples with the tyrosine kinase inhibitor genistein, up to 82.52% and 85.35% GFP ϩ T47D and MCF-7 cells, respectively, were observed. The GFP fluorescence intensity in transduced mammary tumor cells was up to 3 logs higher than that of transduced CD34 ϩ cells. The differential expression of recombinant AAV-2 vectors in hematopoietic and epithelial tumor cells warrants further research with this vector system, including the use of suicide genes for the purging of autologous HSC grafts. Cancer Gene Therapy (2000) 7, 597-604

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confidence: 99%

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

et al. 2000

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“…In BM and PB samples of patients with multiple myeloma could be shown that because of this purification step 99.99% of tumor cells are depleted (log 3.97). 37 For multiple myeloma it could be shown that purged vs un-purged transplants did not result in different disease free or overall survival, suggesting that transplanted tumor cells did not significantly contribute to tumor relapse. 37 The most intense studied genes for chemoprotective gene therapy are MDR1 [6][7][8][9][10] and MGMT.…”

Section: Discussionmentioning

confidence: 99%

“…37 For multiple myeloma it could be shown that purged vs un-purged transplants did not result in different disease free or overall survival, suggesting that transplanted tumor cells did not significantly contribute to tumor relapse. 37 The most intense studied genes for chemoprotective gene therapy are MDR1 [6][7][8][9][10] and MGMT. [24][25][26] As drug combinations are common in most chemotherapeutic regimens, gene therapy with a combination of several genes is particularly promising and would increase the therapeutic index of combination chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

et al. 2009

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Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O 6 -benzylguanine (O 6 -BG)-resistant mutant MGMT P140K (O 6 -methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR 0 SIN-MDR1-IRES-MGMT P140K ), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34 + ). Combination therapy with O 6 -BG/1-(2-chloroethyl)-3-(4-amino-2-methyl pyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34 + cells, monotherapy with O 6 -BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR 0 SIN-MDR1-IRES-MGMT P140K (28.3%). For combination therapy with O 6 -BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMT P140K solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR 0 SIN-MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O 6 -BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drugresistance genes, offering an opportunity to increase the cancer therapeutic index.

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“…[10][11][12][13] In order to reduce the risk of relapse due to the transfer of myeloma cells, several techniques that remove these cells from the transplanted products are being investigated. [14][15][16][17] One such technique is the positive selection of CD34 + cells, shown to contain the necessary precursors for both short-and long-term hematopoietic reconstitution. Since it is believed that the CD34 antigen is not expressed on clonal myeloma cells, selection of CD34 + cells from autologous mobilized peripheral blood progenitor cells may result in the reduction of myeloma contamination of these cells by several orders of magnitude.…”

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Autologous transplantation of mobilized peripheral blood CD34+ cells selected by immunomagnetic procedures in patients with multiple myeloma

Abonour

Scott

Kunkel

et al. 1998

Bone Marrow Transplant

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Summary:In the use of autologous PBPC transplantation in patients with multiple myeloma, contamination of PBPC with myeloma cells is commonly observed. Enrichment for CD34 ؉ cells has been employed as a method of reducing this contamination. In this study the reduction of myeloma cells in PBPC was accomplished by the positive selection of CD34 ؉ cells using immunomagnetic bead separation (Isolex 300 system). PBPC were mobilized from 18 patients using cyclophosphamide (4.5 g/m 2 ) and G-CSF (10 g/kg/day). A median of two leukaphereses and one selection was performed per patient. The median number of mononuclear cells processed was 3.50 × 10 10 with a recovery of 1.11 × 10 8 cells after selection. The median recovery of CD34 ؉ cells was 48% (range 17-78) and purity was 90% (29-99). The median log depletion of CD19 ؉ cells was 3.0. IgH rearrangement, assessed by PCR, was undetectable in 13 of 24 evaluable CD34 ؉ enriched products. Patients received 200 mg/m 2 of melphalan followed by the infusion of a median of 2.91 × 10 6 /kg CD34 ؉ cells (1.00-16.30). The median time to absolute neutrophil count Ͼ0.5 × 10 9 /l was 11 days, and sustained platelet recovery of Ͼ20 × 10 9 /l was 14 days. We conclude that immunomagnetic-based enrichment of CD34 ؉ cells results in a marked reduction in myeloma cells without affecting engraftment kinetics. Keywords: CD34 selection; multiple myeloma; immunomagnetic separation; transplantation The use of standard-dose chemotherapy in the management of multiple myeloma yields unsatisfactory outcomes in terms of both complete response rate and overall survival. In contrast, high-dose chemotherapy and combination chemo-radiotherapy have significantly improved both the disease-free and overall survival rates of patients suffering from multiple myeloma. [1][2][3] This improvement has been seen in both refractory and newly diagnosed patients treated with high-dose chemotherapy and autologous peripheral blood stem cell support. [4][5][6][7] Nonetheless, the high rate of relapse in the setting of autologous transplantation continues to be a major problem. It has been speculated that some of these relapses, particularly early ones, result from the transplantation of clonogenic myeloma cells. 8,9 Indeed, several investigators have shown that peripheral blood progenitor cell (PBPC) products contain significant numbers of circulating clonogenic myeloma cells. [10][11][12][13] In order to reduce the risk of relapse due to the transfer of myeloma cells, several techniques that remove these cells from the transplanted products are being investigated. 14-17 One such technique is the positive selection of CD34 + cells, shown to contain the necessary precursors for both short-and long-term hematopoietic reconstitution. Since it is believed that the CD34 antigen is not expressed on clonal myeloma cells, selection of CD34 + cells from autologous mobilized peripheral blood progenitor cells may result in the reduction of myeloma contamination of these cells by several orders of magnitude. 18,19 We report here ...

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CD34 selection for purging in multiple myeloma and analysis of CD34⁺b cell precursors

Abstract: However, the mean recovery of colony forming precursor cells was only 19% f 8% in the MM samples and 30% i 9% in the control samples. The selection of CD34+ hematopoietic cells is an effective purging method in MM that may be used for autografts, provided the recovery can be improved.

Cited by 33 publications

References 23 publications

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

Autologous transplantation of mobilized peripheral blood CD34+ cells selected by immunomagnetic procedures in patients with multiple myeloma

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CD34 selection for purging in multiple myeloma and analysis of CD34+b cell precursors

Abstract: However, the mean recovery of colony forming precursor cells was only 19% f 8% in the MM samples and 30% i 9% in the control samples. The selection of CD34+ hematopoietic cells is an effective purging method in MM that may be used for autografts, provided the recovery can be improved.

Cited by 33 publications

References 23 publications

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

Differential expression of a recombinant adeno-associated virus 2 vector in human CD34+ cells and breast cancer cells

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

Autologous transplantation of mobilized peripheral blood CD34+ cells selected by immunomagnetic procedures in patients with multiple myeloma

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CD34 selection for purging in multiple myeloma and analysis of CD34⁺b cell precursors