Induction of Macrophage Tumoricidal Activity by Granulocyte-Macrophage Colony-Stimulating Factor

Grabstein, Kenneth H.; Urdal, D L; Tushinski, Robert; Mochizuki, Diane Y.; Price, Virginia L.; Cantrell, Michael A.; Gillis, Steven; Conlon, Paul

doi:10.1126/science.3083507

Cited by 438 publications

(182 citation statements)

References 34 publications

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“…In particular, GM-CSF promotes antibody-dependent cellular cytotoxicity (ADCC) of neutrophils [9] and mononuclear cells [10], increases expression of adhesion molecules on granulocytes and monocytes [11,12] and enhances the antigen-presenting ability of monocytes [13]. These properties suggest that GM-CSF alone [14][15][16] or used in combination therapy may be beneficial in inducing or augmenting tumour regression [17].…”

Section: Introductionmentioning

confidence: 99%

Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy

Wadhwa¹,

Bird²,

Fagerberg

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn this study, the development of neutralizing and non-neutralizing GM-CSF antibodies and the clinical consequences related to the induction of these antibodies were analysed in 20 patients with metastatic colorectal carcinoma receiving a combination therapy of Escherichia coli-derived GM-CSF and a colon carcinoma-reactive MoAb in the absence of any concomitant chemotherapy. The recombinant human GM-CSF was administered subcutaneously for 10 days every month for 4 months. Following the first cycle of treatment, no GM-CSF antibodies were detected, but during subsequent therapy, 19 of the 20 patients studied developed GM-CSF binding antibodies. However, only a proportion (40%) of the 19 antibody-positive patients developed antibodies that neutralized the biological activity of GM-CSF in an in vitro bioassay. The presence of GM-CSF neutralizing antibodies was associated with a significant reduction in GM-CSF-induced expansion of leucocytes, neutrophils and eosinophils. Such clinical effects were not apparent in patients with non-neutralizing antibodies. Further characterization of sera from patients with neutralizing antibodies showed that, in most cases, the antibodies neutralized the biological activity of GM-CSF preparations derived using different expression systems (chinese hamster ovary cells and yeast), suggesting that these antibodies may have the potential to cross-react with endogenously produced GM-CSF. These effects should be considered before therapeutic use of cytokines, particularly in patients who are not immunosuppressed, and therefore capable of mounting an effective immune response. Our results indicate that assessment of production of neutralizing antibodies induced during cytokine therapy can be used to predict diminished clinical response to further therapy.

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Section: Introductionmentioning

confidence: 99%

Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy

Wadhwa¹,

Bird²,

Fagerberg

et al. 1996

Clinical and Experimental Immunology

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“…32,33 GM-CSF released by antigenspecific T cells which reach the tumor site may either potentiate the effect of concomitant produced IFN␥ and other secondary cytokines, and recruit and activate macrophages and granulocytes that are associated with tumor killing through nonspecific bystander effects. 6,34,35 In addition, we showed that GM-CSF can substitute for IFN␥ in inducing rejection of C26/IL-12 injected into IFN␥ KO mice. 36 IL-12 has also been reported to modulate immunodominance of cytotoxic T lymphocytes epitopes coinjected in vivo.…”

Section: Discussionmentioning

confidence: 80%

Cytotoxic T lymphocyte response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12-transduced tumor cell vaccine

et al. 1999

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The colon adenocarcinoma C26, carrying two endogenous related tumor antigens, whereas nonresponders had CTL tumor-associated antigens (TAA) recognized by CTL, has that recognized preferentially the FR␣ antigen. CD8 from been transduced with the gene coding for the human folate responder mice were characterized to release high levels receptor ␣ (FR␣) as an additional antigen in order to study of granulocyte-macrophage (GM)-CSF upon antigen the efficacy of vaccination against a tumor expressing mulstimulation. Tumors obtained from mice that died despite tiple antigens. A dicistronic vector was used to transduce vaccination lost expression of the FR␣ transgene but mainthe IL-12 genes to create C26/IL-12/FR␣ that has been tained expression of endogenous C26 antigens. Immunoused as a cellular vaccine to treat mice bearing lung metselection against FR␣ antigen was not observed in tumors astases of C26/FR␣. After vaccination mice were partially from non-vaccinated controls and from CD8-depleted vacsplenectomized and splenic lymphocytes frozen and used cinated mice. Down-regulation of FR␣ antigen expression retrospectively to study in vitro CD8 T cell response related was due, at least in part, to methylation of retroviral vector to the treatment outcome. Vaccination cured 50% of mice long terminal repeat promoter since FR␣ expression was and the effect was CD8 T cell dependent. Mice either cured partially restored, ex vivo, by treatment with 5-aza-2Ј-(responders) or not cured (nonresponders) by vaccination deoxy-cytidine (aza). These results indicate that CD8 T developed tumor-specific CTL. However, analysis of CTL cell-mediated immunoselection and production of GM-CSF specificity and pCTL frequencies revealed that responders are determining factors for the efficacy of tumor vaccines. had a predominant CTL activity against endogenous C26-

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“…While several studies have shown GM-CSF to be able to prime monocytes by enhancing the release of superoxide, 38 or by stimulating accessory cell function (transcriptional regulation of HLA-DR and IL-1 expression), 39 the role of GM-CSF in enhancing cytotoxicity is still controversial. 40,41 Furthermore, it is still not clear whether GM-CSF activation of monocytes requires a second signal as proposed by Cannistra et al 42 and Hart et al 43 or discussed for IFN-␥. 44 Several groups have shown that combined treatment with GM-CSF and IFN-␥ led to a synergistic tumoricidal activity.…”

Section: Figure 6 Residual Colonies Of U-937 After 2 Weeks Of Cocultumentioning

confidence: 99%

Polyethylenimine-mediated transfection of human monocytes with the IFN-γ gene: an approach for cancer adoptive immunotherapy

Ringenbach¹,

Bohbot²,

Tiberghien³

et al. 1998

Gene Ther

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Human monocytes (Mo) and monocyte-derived macroresponse. To overcome this limitation we have developed phages (MdM) are major effectors in host defense systems a gene transfer protocol with IFN-␥ cDNA and polyethyleniagainst cancer. Their antitumoral activity is dependent mine so as to obtain an efficient, long-lasting autocrine upon two processes: recruitment and activation. One of the cytocidal activation in transfected human Mo/MdM. We most powerful activators for these cells is recombinant show, by clonogenic assays, that efficient transfection and human IFN-␥ (rhIFN-␥). However, when the potential of tumoricidal activity can be obtained by this method in activated rhIFN-␥ was evaluated in clinical trials by ex vivo human monocyte populations. Although the proposed adoptive cellular immunotherapy protocols, the major probmodel must be improved before clinical use, IFN-␥ produclem was the short duration of ex vivo activation by rhIFN-␥.ing monocytes have potential for adoptive immunotherapy. Thus repeated injections were required to obtain a clinical

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Induction of Macrophage Tumoricidal Activity by Granulocyte-Macrophage Colony-Stimulating Factor

Cited by 438 publications

References 34 publications

Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy

Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy

Cytotoxic T lymphocyte response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12-transduced tumor cell vaccine

Polyethylenimine-mediated transfection of human monocytes with the IFN-γ gene: an approach for cancer adoptive immunotherapy

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