Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptidesin vivo

Jäger, Elke; Ringhoffer, Mark; Dienes, Hans Peter; Arand, Michael; Karbach, Julia; Jäger, Dirk; Ilsemann, Christiane; Hagedorn, Manfred; Oesch, Franz; Knuth, Alexander

doi:10.1002/(sici)1097-0215(19960703)67:1<54::aid-ijc11>3.0.co;2-c

Cited by 269 publications

(115 citation statements)

References 22 publications

(22 reference statements)

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“…Our data support the results of Jaeger et al, 22 who found enhanced DTH and CTL responses after i.d. peptide immunization in combination with systemic GM-CSF administration.…”

Section: Discussionsupporting

confidence: 93%

“…in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce efficient T-cell responses against peptide antigens in experimental animals 21 and to enhance T-cell responsiveness to melanoma-associated peptides in melanoma patients and patients with breast and ovarian carcinomas. 22,23 The adjuvant effect of the cytokine GM-CSF is related to the maturation and activation of DCs, which after antigen uptake will move to an adjacent lymph node and activate effector T cells. 16,17,24 To induce anti-ras immunity in patients with pancreatic cancer, we developed a vaccination protocol based on i.d.…”

Section: Abstract: Peptide Vaccination; Pancreatic Cancer; Mutant Ramentioning

confidence: 99%

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Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma

et al. 2001

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K-RAS mutations are frequently found in adenocarcinomas of the pancreas, and induction of immunity against mutant ras can therefore be of possible clinical benefit in patients with pancreatic cancer. We present data from a clinical phase I/II trial involving patients with adenocarcinoma of the pancreas vaccinated by i.d. injection of synthetic mutant ras peptides in combination with granulocyte-macrophage colony-stimulating factor. Forty-eight patients (10 surgically resected and 38 with advanced disease) were treated on an outpatient basis. Peptide-specific immunity was induced in 25 of 43 (58%) evaluable patients, indicating that the protocol used is very potent and capable of eliciting immune responses even in patients with end-stage disease. Patients followed-up for longer periods showed evidence of induction of long-lived immunological memory against the ras mutations. CD4 ؉ T cells reactive with an Arg12 mutation also present in the tumor could be isolated from a tumor biopsy, demonstrating that activated, ras-specific T cells were able to selectively accumulate in the tumor. Vaccination was well tolerated in all patients. Patients with advanced cancer demonstrating an immune response to the peptide vaccine showed prolonged survival from the start of treatment compared to non-responders (median survival 148 days vs. 61 days, respectively; p ‫؍‬ 0.0002). Although a limited number of patients were included in our study, the association between prolonged survival and an immune response against the vaccine suggests that a clinical benefit of ras peptide vaccination may be obtained for this group of patients. © 2001 Wiley-Liss, Inc. Key words: peptide vaccination; pancreatic cancer; mutant ras; granulocyte-macrophage colony-stimulating factor; adenocarcinomaMost patients with pancreatic adenocarcinoma are inoperable at the time of diagnosis. There is currently no effective non-surgical treatment option, and median survival time remains short (3 to 4 months). The small subgroup of operable cases (approx. 10%) has a median survival time of approximately 18 months. 1 Advances in treatment options for patients with pancreatic cancer are urgently needed.Mutations in the proto-oncogenes of the RAS family are frequent in human malignancies, and K-RAS mutations are found in most adenocarcinomas of the pancreas. 2 In addition, the fact that most RAS mutations are confined to codons 12, 13 and 61 3 makes the protein an attractive target for induction of tumor-specific T cells. Previous studies have shown that immune responses to mutated ras peptides and proteins can occur spontaneously in patients with malignancy or can be elicited in normal individuals. 4 -10 Peptide-specific T-cell responsiveness against mutant ras can also be induced in vivo in cancer patients by vaccination with antigen-presenting cells (APCs) loaded ex vivo with ras peptides or ras peptides emulsified in adjuvant. 11,12 These peptides, which are 13 to 17 amino acids in length, represent natural ras epitopes [13][14][15] and are designed primarily to...

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“…Our data support the results of Jaeger et al, 22 who found enhanced DTH and CTL responses after i.d. peptide immunization in combination with systemic GM-CSF administration.…”

Section: Discussionsupporting

confidence: 93%

Section: Abstract: Peptide Vaccination; Pancreatic Cancer; Mutant Ramentioning

confidence: 99%

Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma

et al. 2001

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“…Although immunization with tumor-antigen derived peptides did not induce immune responses, the concomitant administration of GM-CSF elicited delayed type hypersensitivity and T-cell responses [30,31]. The potential of GM-CSF to support the differentiation of monocytes into DCs as a single factor may at least in part be involved in enhancement of the immunological effects induced by the vaccine.…”

Section: Discussionmentioning

confidence: 99%

Activities of granulocyte‐macrophage colony‐stimulating factor and interleukin‐3 on monocytes

et al. 2004

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We examined the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) on human monocytes, using a serum-free culture system. GM-CSF and IL-3 did not promote the differentiation of monocytes into macrophages but rather into cells with a phenotype compatible with that of immature dendritic cells (DCs). The addition of fetal bovine serum to serum-free cultures with GM-CSF or IL-3 restored the differentiation of monocytes into macrophages. Cells generated with GM-CSF or IL-3 elicited phagocytic activity. Cells generated in the presence of GM-CSF or IL-3, followed by the addition of tumor necrosis factor-a, displayed a phenotype of mature DCs, and primed and stimulated immunogenic peptide-specific T lymphocytes. Surprisingly, GM-CSF and IL-3 inhibited macrophage colony-stimulating factor (M-CSF)-dependent differentiation of monocytes into macrophages and induced differentiation into immature DCs. We asked if the inhibition of M-CSF-dependent differentiation into macrophages by GM-CSF or IL-3 was associated with the expression of M-CSF receptors (M-CSFR). GM-CSF or IL-3 down-regulated the expression of M-CSFR. These data demonstrate that GM-CSF and IL-3 primarily support the differentiation of monocytes into DCs and inhibit M-CSF-dependent differentiation into macrophages by suppressing the expression of M-CSFR, thereby promoting differentiation into DCs. Am.

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“…GM-CSF is a commercially available cytokine currently used in patients undergoing chemotherapy to shorten the duration of post-chemotherapy neutropenia. Recently published evidence also suggests that GM-CSF plays an important role as an immune adjuvant [42,43]. The following observations illustrate the mechanisms by which GM-CSF can potentiate the immunogenicity of an antigen: 1) GM-CSF is a key mediator of DC maturation and function [44]; 2) GM-CSF increases surface expression of class I and II MHC molecules as well as costimulatory molecules of DCs in vitro [44]; 3) GM-CSF enhances antibody responses to known immunogens in vivo [45]; 4) tumor cells transfected with genes encoding/expressing GM-CSF are able to induce long lasting, specific anti-tumor immune responses in vivo [46]; and 5) GM-CSF encapsulated in biodegradable microspheres mixed with whole tumor cells resulted in systemic anti-tumor immune responses comparable to those of GM-CSF transfected tumor cells [47].…”

Section: Introductionmentioning

confidence: 99%

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

Mukherjee

Pathangey

Bradley

et al. 2007

Vaccine

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A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan helper peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust antitumor response. The vaccine stimulated IFN-γ-producing CD4 + helper and CD8 + cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

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Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptidesin vivo

Abstract: o 1996 Wiley-Liss, Inc.

Cited by 269 publications

References 22 publications

Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma

Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma

Activities of granulocyte‐macrophage colony‐stimulating factor and interleukin‐3 on monocytes

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

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