Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines play a major role in the regulation of the immune system. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate dendritic cells to present tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies have shown that each of these cytokines alone can induce the regression of tumor cells. In the present study we postulated that peripheral infusion of GM-CSF along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased survival from 9L brain tumors. 9L gliosarcoma cells (10(6)) were implanted in the brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12. Irradiated 9L cells were injected subcutaneously at various time points during treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis were used to further characterize the anti-tumor response. Treatment with GM-CSF and irradiated tumor cells led to an increase in survival rate in rats with intracranial 9L tumors when compared to untreated animals. The addition of IL-2 or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These results suggest that the combined infusion of GM-CSF and other cytokines may be effective adjuvants in treating brain tumors.
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PMID:Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat. 1501 68

Interleukin-2 (IL-2) has been shown to produce durable complete remission in patients with renal cell carcinoma (RCC). A phase 2 study was conducted to evaluate the potential therapeutic synergy as well as the toxic side effects of the concurrent administration of IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced stage disease. Twenty-one patients with unresectable or metastatic RCC having an Eastern Oncology Cooperative Group performance status of 0 or 1 were enrolled. Six patients had received prior immunotherapy with interferon (IFN)-alpha, IFN-gamma, and IL-12, whereas the remaining 15 subjects were previously untreated. Thirteen patients were assigned to a moderate-dose bolus of IL-2 at 72,000 IU/kg every 8 hours on days 1 through 5 and days 15 through 19, whereas 8 patients were given IL-2 as an intravenous continuous infusion at a dose of 5 MU/m2/d on days 1 through 5 and days 15 through 19. Subcutaneous GM-CSF at 125 microg/d on days 1 through 21 was administered concomitantly with IL-2. The median number of IL-2 bolus doses was 23 of a scheduled 28 (85%), whereas with the continuous infusion, 93% of planned IL-2 was given. All patients received 100% of GM-CSF doses. There were no complete or partial responses in this study. Of 13 patients treated in the bolus IL-2 arm, 10 had systemic progression of disease at 4 to 8 weeks, 1 developed metastasis in the brain at 4 weeks, and 2 had stable disease for 4 and 17 months. Among the 8 subjects treated with continuous infusion IL-2, 3 progressed with brain lesions at 3 to 8 weeks and 5 had stable disease at 6+, 7, 8+, 15+, and 17+ months. The median survival for the whole group was 10 months, with a range of 0.5 to 40+ months. There were no regimen-related deaths, and most of the observed toxicities were grade 1 and 2. Serious toxicities (grade 3 and 4) included anemia, atrial fibrillation, oliguria, abnormal liver function, and neurologic events like agitation or confusion. The combination of recombinant IL-2 and GM-CSF administered in the designed schedule and doses was not effective in patients with metastatic RCC and may even interfere with the therapeutic potential of moderate-dose IL-2 and increase its adverse events.
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PMID:A phase 2 study of moderate dose interleukin-2 and granulocyte-macrophage colony-stimulating factor in patients with metastatic or unresectable renal cell carcinoma. 1622 75

Polypeptide and protein immunomodulators are subject to absorption, biodistribution, metabolism and degradation at sites and rates which may not permit effective interactions with components of the immune system. Drug carrier technology can overcome some of these obstacles. Because of the lipid and particulate nature of liposomes, increased delivery of immunomodulators to lymphatics, lymph nodes, lymphatic organs and concentrations of macrophages is possible when an immunomodulator is associated with a liposome. Interleukin-2 (IL-2) liposomes have been shown to have less toxicity and increased immunotherapeutic effects in a number of model systems and are currently in human clinical trials. Local routes such as aerosol delivery to the lung are particularly well suited to use with liposomes containing immunomodulators. Polypeptides can also enhance the interaction of an immunomodulator with the immune system via increased immunostimulation; this can provide a means to enhance oral delivery and to achieve depot effects. Polysaccharide microspheres have been shown to be effective biodegradable carriers of immunomodulators. Finally, genetically engineered bacteria, viruses and mammalian cells may function as delivery systems for immunomodulatory peptides and proteins. Attenuated Salmonella strains can deliver immunomodulators to the gut-associated lymphoid tissue, liver and spleen. In mouse experiments using tumour cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF), irradiated tumour preparations produced GM-CSF and were capable of eliciting effective cell-mediated immune responses, including destruction and elimination of tumour as well as resistance to tumour challenge (i.e. memory response). A wide variety of immunomodulators have been tested using this strategy; IL-2 and GM-CSF are among the most potent inducers of both cell-mediated effector and memory responses. In summary, use of delivery systems can significantly enhance the immunomodulatory potential of polypeptides and proteins.
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PMID:Delivery systems for immunomodulatory proteins and peptides. 1803 Oct 80

Immunotherapy employs cytokines for modifying local inflammatory reactions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to activate dendritic cells, macrophages, and granulocytes leading to clinical trials using GM-CSF-based cancer vaccine approaches. Interleukin-2 (IL-2) is an important T cell stimulatory cytokine approved as exogenous antitumor agent. The ALVAC viral vector system uses a recombinant canarypox virus for local gene expression. We report a phase I clinical trial using intratumoral administration of ALVAC GM-CSF or ALVAC IL-2 in skin metastases of melanoma or leiomyosarcoma. ALVAC GM-CSF and ALVAC IL-2 were injected at 107.12 and 106.92, 50% cell culture infectious dose in eight metastases with acceptable tolerability. Local and systemic inflammatory reactions were observed. The transgene determined the local infiltrate: GM-CSF induced monocyte and macrophage enrichment of the peritumoral inflammatory infiltrate, whereas IL-2 increased local T lymphocytes. Stable disease of injected lesions was seen after ALVAC GM-CSF application, whereas ALVAC IL-2 treatment led to partial regression in three out of eight injected tumors, accompanied by decreased expression of melanocytic antigens. Local GM-CSF expression could be induced. In summary, ALVAC GM-CSF and ALVAC IL-2 injections are safe and can mediate local biologic and immunologic effects.
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PMID:Clinical phase I intratumoral administration of two recombinant ALVAC canarypox viruses expressing human granulocyte-macrophage colony-stimulating factor or interleukin-2: the transgene determines the composition of the inflammatory infiltrate. 1833 46

Thus far, peptide vaccines used to stimulate tumor-specific immune responses in patients with melanoma have been largely unsuccessful. Granulocyte-macrophage colony-stimulating factor and interleukin-2 are immune-potentiating cytokines that have improved vaccine responses in preclinical models. We hypothesized that higher doses of granulocyte-macrophage colony-stimulating factor and addition of low-dose interleukin-2 might augment responses to vaccine antigens. Patients with resected stage II, III, or IV melanoma were treated with vaccines containing three melanoma-associated peptides [MART-1a, gp100(207-217), and survivin], along with 300 or 500 mcg granulocyte-macrophage colony-stimulating factor in Montanide ISA. Cohorts of patients received low-dose subcutaneous interleukin-2 on days 7-20 after vaccination. Induction of a response was defined as either doubling of cytotoxic T lymphocyte frequency from baseline or increase in frequency from undetectable (<0.05%) to detectable. Leukocyte subsets and plasma cytokines were analyzed before and after vaccination. Cytotoxic T lymphocyte responses to MART-1a, gp100(207-217), and survivin were induced in 11, 16, and 14 of 19 patients, respectively. Responses were not higher in patients receiving 500 mcg granulocyte-macrophage colony-stimulating factor or low-dose interleukin-2 than in patients receiving 300 mcg granulocyte-macrophage colony-stimulating factor only. Interleukin-2 treatment (in nine patients) led to increases in natural killer cells and T regulatory cells compared with no interleukin-2 treatment (nine patients). Multiple plasma cytokines were transiently induced during vaccination. Neither increasing the dose of granulocyte-macrophage colony-stimulating factor nor addition of low-dose interleukin-2 resulted in an increase in the frequency of vaccine-specific cytotoxic T lymphocytes to a melanoma peptide vaccine. The increase in T regulatory cells associated with interleukin-2 treatment suggests that interleukin-2 may be immunosuppressive in this setting.
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PMID:Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine. 2169 48


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