RESUMO
Pancreatic cancer has a dismal prognosis, and treatment options for patients with locally advanced or metastatic disease are limited. Early tumor progression after standard chemo- and or radiotherapy remains a major concern in managing these patients. Treating pancreatic cancer patients with the Toll-like receptor 3 (TLR-3) agonist rintatolimod (Ampligen®) was effective in boosting the immune response. Rintatolimod acts via the TLR-3 receptor on several immune cells. However, the TLR-3 expression pattern in pancreatic cancer cells and how rintatolimod affects pancreatic cancer cells have not yet been investigated. The TLR-3 protein and mRNA expression were evaluated in thirteen PDAC tissue samples as well as in the human PDAC (hPDAC) cell lines CFPAC-1, MIAPaCa-2, and PANC-1 using immunohistochemistry and multiplexed gene expression analysis, respectively. The direct anti-tumor effects of rintatolimod were investigated using a proliferation and migration assay after different incubation time points with increasing concentrations of rintatolimod (ranging from 0.05 to 0.4 mg/ml). The TLR-3 protein and mRNA expression were heterogeneous between the PDAC tissue samples and the three hPDAC cell lines. TLR-3 protein and mRNA expression were high in CFPAC-1, moderate in MIAPaCa-2, and undetectable in PANC-1. Rintatolimod three-day treatment resulted in significantly reduced proliferation of CFPAC-1 cells compared to vehicle-treated control cells. In addition, after 24 hours, rintatolimod-treated CFPAC-1 cells showed less cell migration compared to vehicle-treated control cells, although this difference was not statistically significant. Lastly, we identified fifteen genes, altered with a Log2 FOC > |1.0| in rintatolimod-treated CFPAC-1 cells, which were significantly related to three transcription factors (NFKB1, RELA, and SP1) regulating the TLR-3 signaling pathway. In conclusion, we propose that rintatolimod treatment might have a direct TLR-3-dependent anti-tumoral effect on pancreatic cancer cells expressing TLR-3.
RESUMO
Accumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.
Assuntos
Imunoterapia , Neoplasias , Ligantes , Adjuvantes Imunológicos , Proteínas de Membrana , Proteínas de Neoplasias , Receptores Toll-LikeRESUMO
Ebola virus (EBOV) is a highly infectious and lethal pathogen responsible for sporadic self-limiting clusters of Ebola virus disease (EVD) in Central Africa capable of reaching epidemic status. 100% protection from lethal EBOV-Zaire in Balb/c mice was achieved by rintatolimod (Ampligen) at the well tolerated human clinical dose of 6 mg/kg. The data indicate that the mechanism of action is rintatolimod's dual ability to act as both a competitive decoy for the IID domain of VP35 blocking viral dsRNA sequestration and as a pathogen-associated molecular pattern (PAMP) restricted agonist for direct TLR3 activation but lacking RIG-1-like cytosolic helicase agonist properties. These data show promise for rintatolimod as a prophylactic therapy against human Ebola outbreaks.
Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Animais , Camundongos , Humanos , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/prevenção & controle , Receptor 3 Toll-Like , Proteínas Virais Reguladoras e Acessórias , Poli I-C , Ebolavirus/genéticaRESUMO
Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.
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Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.
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Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA). Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2'-5' adenylate synthetase, protein kinase R). Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.
Assuntos
Síndrome de Fadiga Crônica/tratamento farmacológico , Poli I-C/uso terapêutico , Poli U/uso terapêutico , Receptor 3 Toll-Like/agonistas , Animais , Síndrome de Fadiga Crônica/fisiopatologia , Humanos , Imunidade Inata/imunologia , Poli I-C/efeitos adversos , Poli I-C/farmacologia , Poli U/efeitos adversos , Poli U/farmacologia , RNA de Cadeia Dupla/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Pathogen-associated molecular patterns (PAMPs) are stand-alone immunomodulators or 'danger signals,' that are increasingly recognized as critical components of many modern vaccines. Polyinosinic-polycytidylic acid (poly-IC) is a synthetic dsRNA that can activate multiple elements of the host defense in a pattern that parallels that of a viral infection. When properly combined with an antigen, it can be utilized as a PAMP-adjuvant, resulting in modulation and optimization of the antigen-specific immune response. We briefly review the preclinical and clinical uses of poly-IC and two poly-IC derivatives, poly-IC12U (Ampligen) and poly-ICLC (Hiltonol), as vaccine adjuvants.
Assuntos
Adjuvantes Imunológicos/farmacologia , Poli I-C/farmacologia , Vacinas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Humanos , Poli I-C/administração & dosagem , Vacinas/administração & dosagemRESUMO
Current research and development of antigens for vaccination often center on purified recombinant proteins, viral subunits, synthetic oligopeptides or oligosaccharides, most of them suffering from being poorly immunogenic and subject to degradation. Hence, they call for efficient delivery systems and potent immunostimulants, jointly denoted as adjuvants. Particulate delivery systems like emulsions, liposomes, nanoparticles and microspheres may provide protection from degradation and facilitate the co-formulation of both the antigen and the immunostimulant. Synthetic double-stranded (ds) RNA, such as polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a mimic of viral dsRNA and, as such, a promising immunostimulant candidate for vaccines directed against intracellular pathogens. Poly(I:C) signaling is primarily dependent on Toll-like receptor 3 (TLR3), and on melanoma differentiation-associated gene-5 (MDA-5), and strongly drives cell-mediated immunity and a potent type I interferon response. However, stability and toxicity issues so far prevented the clinical application of dsRNAs as they undergo rapid enzymatic degradation and bear the potential to trigger undue immune stimulation as well as autoimmune disorders. This review addresses these concerns and suggests strategies to improve the safety and efficacy of immunostimulatory dsRNA formulations. The focus is on technological means required to lower the necessary dosage of poly(I:C), to target surface-modified microspheres passively or actively to antigen-presenting cells (APCs), to control their interaction with non-professional phagocytes and to modulate the resulting cytokine secretion profile.
Assuntos
Adjuvantes Imunológicos/química , Poli I-C/química , Vacinas/química , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos/administração & dosagem , Antígenos/química , Células Dendríticas/imunologia , Humanos , Microesferas , Poli I-C/administração & dosagem , Receptor 3 Toll-Like/imunologia , Vacinas/administração & dosagemAssuntos
Termos de Consentimento , Contratos , Indústria Farmacêutica , Drogas em Investigação , Regulamentação Governamental , Experimentação Humana , Consentimento Livre e Esclarecido , Jurisprudência , Sujeitos da Pesquisa , Pesquisa , Controle Social Formal , Experimentação Humana Terapêutica , United States Food and Drug Administration , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Economia , Síndrome de Fadiga Crônica , Governo Federal , Governo , Humanos , Responsabilidade Legal , Distribuição Aleatória , Estados UnidosAssuntos
Termos de Consentimento , Contratos , Indústria Farmacêutica , Drogas em Investigação , Experimentação Humana , Consentimento Livre e Esclarecido , Jurisprudência , Sujeitos da Pesquisa , Pesquisa , Experimentação Humana Terapêutica , Economia , Síndrome de Fadiga Crônica , Governo Federal , Governo , Regulamentação Governamental , Humanos , Responsabilidade Legal , Pesquisadores , Controle Social Formal , Estados Unidos , United States Food and Drug AdministrationAssuntos
Termos de Consentimento , Contratos , Indústria Farmacêutica , Drogas em Investigação , Experimentação Humana , Consentimento Livre e Esclarecido , Jurisprudência , Sujeitos da Pesquisa , Pesquisa , Experimentação Humana Terapêutica , Comissão de Ética , Comitês de Ética em Pesquisa , Síndrome de Fadiga Crônica , Humanos , Responsabilidade Legal , Nevada , PesquisadoresRESUMO
KIE: The plaintiff, Daniel DeVito, volunteered to participate in clincial investigations of a new AIDS drug, Ampligen. After three unrevealing experiments, the defendants -- HEM, Inc., DuPont, Inc., Hahnemann University, and the Food and Drug Administration -- determined the drug was ineffective and terminated further testing. The plaintiff sued to prevent termination claiming the treatment was keeping him alive. He filed for a temporary restraining order. The court denied the request, dismissing the case for lack of jurisdiction. Because termination was not made pursuant to Congressional act, but rather at the sponsors' discretion, no putatively illegal conduct was likely to be redressed by the order. The court found that legally required notice was given, and the consent forms signed did not give the plaintiff the implicit right to be provided with Ampligen.^ieng