Immunotherapy with acute leukemia cells modified into antigen-presenting cells: ex vivo culture and gene transfer methods

Stripecke, Renata; Levine, A. Joan; Pullarkat, Vinod; Cardoso, A. A.

doi:10.1038/sj.leu.2402701

Cited by 43 publications

(32 citation statements)

References 90 publications

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“…The achievement of a state of minimal residual disease following ABMT may also be an ideal platform for a variety of noncross-resistant strategies, including immunotherapeutic approaches, to eradicate residual leukemia. 20,21 We identified age and cytogenetic risk as the most important determinants of overall survival after ABMT for AML in first remission, findings observed by others. 6,7,[22][23][24] Of interest was the excellent outcome of the good-risk group with an 8-year overall survival of 93%, a group for whom allogeneic and autologous stem cell transplantation is normally withheld.…”

Section: Discussionsupporting

confidence: 52%

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Mollee

Gupta

Song

et al. 2004

Bone Marrow Transplant

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Summary:Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (Po0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P ¼ 0.04) and cytogenetic risk group (P ¼ 0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.

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Section: Discussionsupporting

confidence: 52%

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Mollee

Gupta

Song

et al. 2004

Bone Marrow Transplant

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“…In an attempt to specifically target leukemic cells, therapeutic AML vaccines based on modified AML cells are currently under active investigation. [2][3][4][5] The poor immunogenicity of AML cells represents a major hurdle for immunotherapy. 6 Strategies to enhance this immunogenicity include gene transfer in AML cells to increase the expression of costimulatory molecules and the secretion of proinflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells

et al. 2007

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Leukemic cells exert immunosuppressive effects that interfere with dendritic cell (DC) function and hamper effective antileukemic immune responses. Here, we sought to enhance the immunogenicity of leukemic cells by loading them with the double-stranded (ds) RNA Toll-like receptor 3 (TLR3) ligand polyriboinosinic polyribocytidylic acid (poly(I:C)), mimicking viral infection of the tumor cells. Given the responsiveness of DC to TLR ligands, we hypothesized that the uptake of poly(I:C)-loaded leukemic cells by immature DC (iDC) would lead to DC activation. Primary acute myeloid leukemia (AML) cells and AML cell lines markedly responded to poly(I:C) electroporation by apoptosis, upregulation of TLR3 expression, enhanced expression of major histocompatibility complex (MHC) and costimulatory molecules and by production of type I interferons (IFN). Upon phagocytosis of poly(I:C)-electroporated AML cells, DC maturation and activation were induced as judged by an increased expression of MHC and costimulatory molecules, production of proinflammatory cytokines and an increase of T helper 1 (T H 1)-polarizing capacity. These immune effects were suboptimal when AML cells were passively pulsed with poly(I:C), indicating the superiority of poly(I:C) transfection over pulsing. Our results demonstrate that poly(I:C) electroporation is a promising strategy to increase the immunogenicity of AML cells and to convert iDC into activated mature DC following the phagocytosis of AML cells.

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“…1 Immunotherapy represents one of the more promising approaches for the treatment of nonresponsive ALL. 2,3 Nevertheless, very few reports address the issue of transferring a functional gene into fresh samples of ALL to increase immune recognition of the blasts by the patient's immune system. [4][5][6] Among the current technologies for gene transfer of leukemia cells, the latest generation of HIV-1-based lentiviral vectors represent the most efficient tool for their reported ability to transduce with stability, a wide variety of cell types in significant percentages.…”

mentioning

confidence: 99%

Functional transfer of CD40L gene in human B-cell precursor ALL blasts by second-generation SIN lentivectors

et al. 2003

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Three different second-generation lentiviral self-inactivating vectors containing CMV, EF1a and PGK promoter, respectively, and all carrying the exogenous GFP gene, were compared for expression in human B-cell precursor ALL blasts. At a comparable percentage of transduction and vector DNA copy number, CMV clearly showed better efficiency of transcription. Human bone marrow stromal cells were favored compared to the MRC-5 cell line, as support for cell viability during infection. Cells were infected and analyzed after variable culture times ranging from 4 to 12 days, to reduce the possibility of pseudotransduction. In 10/ 14 samples, we detected more than 20% GFP-positive cells after exposure to high-titer viral supernatants. We then tested a similar vector carrying the human CD40L cDNA and, in similar infection conditions, obtained more than 20% transduction in 6/6 samples. The levels of transduction obtained were sufficient to induce the upregulation of CD83 molecule in cocultured immature dendritic cells.

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Immunotherapy with acute leukemia cells modified into antigen-presenting cells: ex vivo culture and gene transfer methods

Cited by 43 publications

References 90 publications

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells

Functional transfer of CD40L gene in human B-cell precursor ALL blasts by second-generation SIN lentivectors

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