RESUMO
BACKGROUND: Erenumab is a monoclonal antibody specifically targeting the CGRP-receptor. Several studies showed efficacy and safety in patients with migraine. Less is known regarding dosage increase, especially in a difficult to treat patients. The aim of the study is to evaluate the increased dosage under real world conditions with particular focus on 70 mg non-responders. METHODS: In a retrospective analysis, patients treated in tertiary headache centers (Halle or Jena, Germany) receiving 70 mg erenumab for at least 3 months with a dosage increase to 140 mg were analyzed. Data were evaluated regarding headache days, intake of acute medication, previous prophylaxis, and medication overuse. Baseline and all treatment intervals were determined as three-month periods. RESULTS: Datasets of 52 migraine patients (90.4% women) aged between 22 and 78 years (mean 50.4 years, SD 12.1 years) were analyzed. At baseline (mean headache-days 15.67 ± 6.37) 51.9% met criteria for chronic migraine and 56% were currently overusing acute medication. While therapy with 70 mg showed significant improvement in headache days and 50% response, further improvement was not achieved for therapy escalation to 140 mg. The same applies to the secondary endpoints and covers the entire study population as well as the subgroups of chronic and episodic migraine. The 50% response of the 70 mg non-responders for escalation was only 5.14%. CONCLUSIONS: In this difficult-to-treat patient cohort we reconfirmed the effectiveness of erenumab, but could not detect any additional benefit for a dosage escalation from 70 mg to 140 mg erenumab.
RESUMO
BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is an anticancer modality approved for the treatment of early disease and palliation of late stage disease. PDT of tumors results in the generation of an acute inflammatory response. The extent and duration of the inflammatory response is dependent upon the PDT regimen employed and is characterized by rapid induction of proinflammatory cytokines, such as IL-6, and activation and mobilization of innate immune cells. The importance of innate immune cells in long-term PDT control of tumor growth has been well defined. In contrast the role of IL-6 in long-term tumor control by PDT is unclear. Previous studies have shown that IL-6 can diminish or have no effect on PDT antitumor efficacy. STUDY DESIGN/MATERIALS AND METHODS: In the current study we used mice deficient for IL-6, Il6(-/-) , to examine the role of IL-6 in activation of antitumor immunity and PDT efficacy by PDT regimens known to enhance antitumor immunity. RESULTS: Our studies have shown that elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor draining lymph node (TDLN) and did not affect primary antitumor T-cell activation by PDT. However, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models. The inhibition of PDT efficacy by IL-6 appears also to be related to regulation of Bax protein expression. Increased apoptosis was observed following treatment of tumors in Il6(-/-) mice 24 hours following PDT. CONCLUSIONS: The development of PDT regimens that enhance antitumor immunity has led to proposals for the use of PDT as an adjuvant treatment. However, our results show that the potential for PDT induced expression of IL-6 to enhance tumor survival following PDT must be considered.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/imunologia , Interleucina-6/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Clorofila/análogos & derivados , Clorofila/imunologia , Clorofila/farmacocinética , Clorofila/farmacologia , Neoplasias do Colo/imunologia , Éter de Diematoporfirina/imunologia , Éter de Diematoporfirina/farmacocinética , Éter de Diematoporfirina/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Fármacos Fotossensibilizantes/imunologia , Fármacos Fotossensibilizantes/farmacocinética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Chronic inflammation leads to the formation of a pro-tumorigenic microenvironment that can promote tumor development, growth and differentiation through augmentation of tumor angiogenesis. Prostate cancer (CaP) risk and prognosis are adversely correlated with a number of inflammatory and angiogenic mediators, including Toll-like receptors (TLRs), NF-κB and vascular endothelial growth factor (VEGF). Peroxiredoxin 1 (Prx1) was recently identified as an endogenous ligand for TLR4 that is secreted from CaP cells and promotes inflammation. Inhibition of Prx1 by CaP cells resulted in reduced expression of VEGF, diminished tumor vasculature and retarded tumor growth. The mechanism by which Prx1 regulates VEGF expression in normoxic conditions was investigated in the current study. Our results show that incubation of mouse vascular endothelial cells with recombinant Prx1 caused increases in VEGF expression that was dependent upon TLR4 and required hypoxia inducible factor-1 (HIF-1) interaction with the VEGF promoter. The induction of VEGF was also dependent upon NF-κB; however, NF-κB interaction with the VEGF promoter was not required for Prx1 induction of VEGF suggesting that NF-κB was acting indirectly to induce VEGF expression. The results presented here show that Prx1 stimulation increased NF-κB interaction with the HIF-1α promoter, leading to enhanced promoter activity and increases in HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. Prx1 induced HIF-1 also promoted NF-κB activity, suggesting the presence of a positive feedback loop that has the potential to perpetuate Prx1 induction of angiogenesis. Strikingly, inhibition of Prx1 expression in CaP was accompanied with reduced expression of HIF-1α. The combined findings of the current study and our previous study suggest that Prx1 interaction with TLR4 promotes CaP growth potentially through chronic activation of tumor angiogenesis.
Assuntos
Endotélio Vascular/metabolismo , Proteínas de Homeodomínio/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , NF-kappa B/genética , Neoplasias da Próstata/irrigação sanguínea , Receptor 4 Toll-Like/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Linhagem Celular Tumoral , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/imunologia , Proteínas de Homeodomínio/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Masculino , Camundongos , Camundongos SCID , NF-kappa B/imunologia , Transplante de Neoplasias , Neovascularização Patológica , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Ligação Proteica , RNA Interferente Pequeno/genética , Transdução de Sinais , Receptor 4 Toll-Like/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
Photodynamic therapy (PDT) is a Food and Drug Administration-approved local cancer treatment that can be curative of early disease and palliative in advanced disease. PDT of murine tumors results in regimen-dependent induction of an acute local inflammatory reaction, characterized in part by rapid neutrophil infiltration into the treated tumor bed. In this study, we show that a PDT regimen that induced a high level of neutrophilic infiltrate generated tumor-specific primary and memory CD8(+) T-cell responses. In contrast, immune cells isolated from mice treated with a PDT regimen that induced little or no neutrophilic infiltrate exhibited minimal antitumor immunity. Mice defective in neutrophil homing to peripheral tissues (CXCR2(-/-) mice) or mice depleted of neutrophils were unable to mount strong antitumor CD8(+) T-cell responses following PDT. Neutrophils seemed to be directly affecting T-cell proliferation and/or survival rather than dendritic cell maturation or T-cell migration. These novel findings indicate that by augmenting T-cell proliferation and/or survival, tumor-infiltrating neutrophils play an essential role in establishment of antitumor immunity following PDT. Furthermore, our results may suggest a mechanism by which neutrophils might affect antitumor immunity following other inflammation-inducing cancer therapies. Our findings lay the foundation for the rational design of PDT regimens that lead to optimal enhancement of antitumor immunity in a clinical setting. Immune-enhancing PDT regimens may then be combined with treatments that result in optimal ablation of primary tumors, thus inhibiting growth of primary tumor and controlling disseminated disease.
Assuntos
Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neutrófilos/fisiologia , Fotoquimioterapia , Animais , Antígeno CD11b/análise , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Células Dendríticas/fisiologia , Inflamação/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-8B/fisiologiaRESUMO
BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) efficacy appears to be enhanced in the presence of an intact immune system and PDT has been shown to augment anti-tumor immunity. The mechanisms leading to the enhancement of the host immune response to tumor are unclear. Anti-tumor immunity depends upon the presence of activated antigen presenting cells (APCs). These cells are activated by their recognition of components released by pathogens, viruses, dead cells, and the presence of pro-inflammatory mediators. Activated APCs stimulate the generation of cytokine secreting effector cells. Therefore, we have hypothesized that PDT generated inflammatory mediators and components released from tumor cells killed by PDT results in the activation of APCs capable of stimulating effector T-cell proliferation and cytokine secretion. STUDY DESIGN/MATERIALS AND METHODS: To determine the effect of PDT on APCs, tumor draining lymph nodes (TDLNs) of EMT6 or Colo 26 tumor bearing mice were isolated 24 hours after Photofrin-PDT and flow cytometry was used to detect the presence of APCs secreting the T cells stimulatory cytokine, IL-12. APCs were also isolated from TDLNs and used to stimulate T-cell proliferation and secretion of interferon-gamma (IFN-gamma). RESULTS: PDT results in an increase in IL-12 expressing APCs in the TDLN. This increase was accompanied by an increase in the ability of APCs isolated from TDLNs of PDT-treated mice to stimulate T-cell proliferation and T-cell secretion of IFN-gamma. CONCLUSIONS: Our results indicate that APCs isolated from PDT-treated mice exhibit an enhanced ability to stimulate T-cell proliferation and IFN-gamma secretion, suggesting that PDT results in increased APC activity.