Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing tumor vaccines

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3011-3019
Author(s):  
Ivan Borrello ◽  
Eduardo M. Sotomayor ◽  
Frédérique-Marie Rattis ◽  
Sara K. Cooke ◽  
Lingping Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Tumor Cells ◽  
Immune Reconstitution ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

For many cancers, autologous bone marrow transplantation (BMT) achieves a minimal residual disease state, yet relapse rates remain high. Using a syngeneic murine bone marrow transplant model, we demonstrate that vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing autologous tumor cells is effective in the post-BMT period and actually results in a greater tumor-free survival than vaccination in the nontransplant setting. Employing T cells specific for a model tumor-antigen, we find that transplantation of the tumor-bearing host results in a massive expansion and activation of tumor-specific T cells in the early posttransplant period, but this response rapidly declines in association with tumor progression. Immunization with irradiated GM-CSF tumor cells during the period of immune reconstitution results in the sustained amplification and activation of this response that closely correlates with freedom from relapse. These results demonstrate the feasibility of integrating GM-CSF vaccines in the postautologous BMT setting and suggest mechanisms that may contribute to the observed efficacy of immunization during the critical period of immune reconstitution.

Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing tumor vaccines

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3011-3019 ◽  
Author(s):  
Ivan Borrello ◽  
Eduardo M. Sotomayor ◽  
Frédérique-Marie Rattis ◽  
Sara K. Cooke ◽  
Lingping Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Tumor Cells ◽  
Immune Reconstitution ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract For many cancers, autologous bone marrow transplantation (BMT) achieves a minimal residual disease state, yet relapse rates remain high. Using a syngeneic murine bone marrow transplant model, we demonstrate that vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing autologous tumor cells is effective in the post-BMT period and actually results in a greater tumor-free survival than vaccination in the nontransplant setting. Employing T cells specific for a model tumor-antigen, we find that transplantation of the tumor-bearing host results in a massive expansion and activation of tumor-specific T cells in the early posttransplant period, but this response rapidly declines in association with tumor progression. Immunization with irradiated GM-CSF tumor cells during the period of immune reconstitution results in the sustained amplification and activation of this response that closely correlates with freedom from relapse. These results demonstrate the feasibility of integrating GM-CSF vaccines in the postautologous BMT setting and suggest mechanisms that may contribute to the observed efficacy of immunization during the critical period of immune reconstitution.

scholarly journals Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation

2008 ◽  
Vol 295 (1) ◽  
pp. L114-L122 ◽  
Author(s):  
Megan N. Ballinger ◽  
Leah L. N. Hubbard ◽  
Tracy R. McMillan ◽  
Galen B. Toews ◽  
Marc Peters-Golden ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Host Defense ◽  
Receptor Expression ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Bacterial Killing ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E2(PGE2) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF−/− donors (GM-CSF−/− BMT) with untransplanted mice. GM-CSF−/− BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF−/− BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF−/− BMT mice overproduced PGE2, but expression of the inhibitory EP2receptor was diminished. As a consequence of decreased EP2receptor expression, we found diminished accumulation of cAMP in response to PGE2stimulation in GM-CSF−/− BMT AMs compared with control BMT AMs. In addition, GM-CSF−/− BMT AMs retained cysteinyl leukotriene production and normal TNF-α response compared with AMs from control BMT mice. GM-CSF−/− BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF−/− recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.

scholarly journals NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

1990 ◽  
Vol 10 (3) ◽  
pp. 1281-1286 ◽  
Author(s):  
R Schreck ◽  
P A Baeuerle
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma

2003 ◽  
Vol 21 (17) ◽  
pp. 3343-3350 ◽  
Author(s):  
Robert Soiffer ◽  
F. Stephen Hodi ◽  
Frank Haluska ◽  
Ken Jung ◽  
Silke Gillessen ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Metastatic Melanoma ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Melanoma Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 × 106, 4 × 106, or 1 × 107tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

scholarly journals Expression of the macrophage-specific colony-stimulating factor in human monocytes treated with granulocyte-macrophage colony-stimulating factor

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1259-1261
Author(s):  
J Horiguchi ◽  
MK Warren ◽  
D Kufe
Keyword(s):  
T Cells ◽  
Gene Product ◽  
Phorbol Ester ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Activated Monocytes ◽  
Macrophage Colony ◽  
Stimulating Factor

The macrophage-specific colony-stimulating factor (CSF-1, M-CSF) regulates the survival, growth and differentiation of monocytes. We have recently demonstrated that phorbol ester induces expression of CSF- 1 in human monocytes. These findings suggested that activated monocytes are capable of producing their own lineage-specific CSF. The present studies demonstrate that the granulocyte-macrophage colony-stimulating factor (GM-CSF) also induces CSF-1 transcripts in monocytes. Furthermore, we demonstrate that the detection of CSF-1 RNA in GM-CSF- treated monocytes is associated with synthesis of the CSF-1 gene product. The results thus suggest that GM-CSF may indirectly control specific monocyte functions through the regulation of CSF-1 production. These findings indicate another level of interaction between T cells and monocytes.

scholarly journals Differentiation of human dendritic cells from monocytes in vitro using granulocyte-macrophage colony stimulating factor and low concentration of interleukin-4

2003 ◽  
Vol 60 (5) ◽  
pp. 531-538 ◽  
Author(s):  
Miodrag Colic ◽  
Dusan Jandric ◽  
Zorica Stojic-Vukanic ◽  
Jelena Antic-Stankovic ◽  
Petar Popovic ◽  
...  
Keyword(s):  
T Cells ◽  
Interleukin 4 ◽  
Adherent Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Alloreactive T Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Dendritic Cells ◽  
Stimulating Factor

Several laboratories have developed culture systems that allow the generation of large numbers of human dendritic cells (DC) from monocytes using granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-4 (IL-4). In this work we provided evidence that GM-CSF (100 ng/ml) in combination with a low concentration of IL-4 (5 ng/ml) was efficient in the generation of immature, non-adherent, monocyte-derived DC as the same concentration of GM-CSF, and ten times higher concentration of IL-4 (50 ng/ml). This conclusion was based on the similar phenotype profile of DC such as the expression of CD1a, CD80, CD86, and HLA-DR, down-regulation of CD14, and the absence of CD83, as well as on their similar allostimulatory activity for T cells. A higher number of cells remained adherent in cultures with lower concentrations of IL-4 than in cultures with higher concentrations of the cytokine. However, most of these adherent cells down-regulated CD14 and stimulated the proliferation of alloreactive T cells. In contrast adherent cells cultivated with GM-CSF alone were predominantly macrophages as judged by the expression of CD14 and the inefficiency to stimulate alloreactive T cells. DC generated in the presence of lower concentrations of IL-4 had higher proapoptotic potential for the Jurkat cell line than DC differentiated with higher concentrations of IL-4, suggesting their stronger cytotoxic, anti-tumor effect.

scholarly journals Heparin inhibits the expression of interleukin-11 and granulocyte- macrophage colony-stimulating factor in primate bone marrow stromal fibroblasts through mRNA destabilization

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2526-2533 ◽  
Author(s):  
L Yang ◽  
YC Yang
Keyword(s):  
Bone Marrow ◽  
Extracellular Matrix ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Extracellular Matrix Components ◽  
Macrophage Colony Stimulating Factor ◽  
Mrna Destabilization ◽  
Matrix Components ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Interactions between different cytokines, extracellular matrix components, and various cell types inside the bone marrow microenvironment are believed to play important roles in the regulation of hematopoiesis. We observed that both interleukin-1 (IL-1) and 12-O- tetradecanoylphorbol-13-acetate (TPA) can stimulate the expression of IL-11 and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in a primate bone marrow stromal fibroblast cell line, PU-34. We also found that IL-1 or TPA-stimulated IL-11 and GM-CSF expression in PU-34 cells can be abolished by heparin, a class of molecules related to extracellular matrix components, glycosaminoglycans. Because the growth inhibitory signals provided by extracellular factors were less understood, the mechanisms of heparin inhibition of IL-11 and GM-CSF gene expression were further investigated. Our data demonstrate for the first time that heparin did not alter the transcription of endogenous IL-11 and GM-CSF genes or an exogenous IL-11 promoter construct containing an AP-1 sequence. Instead, heparin facilitated the degradation of the corresponding mRNAs. Through RNA gel shift assays, heparin-mediated mRNA destabilization was tentatively linked to its competition for mRNA binding proteins both in the cell-free system and in intact cells. Collectively, our findings suggest that varying degrees of heparin inhibition may provide a novel mechanism for the regulation of cytokine expression during the growth and differentiation of different lineages of hematopoietic cells.

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