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1.
J Pathol ; 249(1): 52-64, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30972766

RESUMO

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have improved the survival of patients with non-small cell lung cancer (NSCLC). Still, many patients do not respond to these inhibitors. PD-L1 (CD274) expression, one of the factors that influences the efficacy of immune checkpoint inhibitors, is dynamic. Here, we studied the regulation of PD-L1 expression in NSCLC without targetable genetic alterations in EGFR, ALK, BRAF, ROS1, MET, ERBB2 and RET. Analysis of RNA sequencing data from these NSCLCs revealed that inferred IFNγ, EGFR and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma. In a representative lung adenocarcinoma cell line panel, stimulation with EGF or IFNγ increased CD274 mRNA and PD-L1 protein and membrane levels, which were further enhanced by combining EGF and IFNγ. Similarly, tumor cell PD-L1 membrane levels increased after coculture with activated peripheral blood mononuclear cells. Inhibition of the MAPK pathway, using EGFR inhibitors cetuximab and erlotinib or the MEK 1 and 2 inhibitor selumetinib, prevented EGF- and IFNγ-induced CD274 mRNA and PD-L1 protein and membrane upregulation, but had no effect on IFNγ-induced MHC-I upregulation. Interestingly, although IFNγ increases transcriptional activity of CD274, MAPK signaling also increased stabilization of CD274 mRNA. In conclusion, MAPK pathway activity plays a key role in EGF- and IFNγ-induced PD-L1 expression in lung adenocarcinoma without targetable genetic alterations and may present a target to improve the efficacy of immunotherapy. © 2019 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Antígeno B7-H1/genética , Técnicas de Cocultura , Fator de Crescimento Epidérmico/farmacologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Interferon gama/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Inibidores de Proteínas Quinases/farmacologia , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
2.
J Immunother Cancer ; 10(8)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35922089

RESUMO

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.


Assuntos
Imunoterapia , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Humanos , Imunoterapia/métodos , Imagem Molecular , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Tomografia por Emissão de Pósitrons/métodos
3.
BMC Cancer ; 11: 39, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21272366

RESUMO

BACKGROUND: rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether agonistic DR4 or DR5 antibodies could be used to circumvent rhTRAIL resistance, alone or in combination with various chemotherapies. METHODS: Our study was performed in an isogenic model comprised of the SW948 human colon carcinoma cell line and its rhTRAIL resistant sub-line SW948-TR. Effects of rhTRAIL and agonistic DR4/DR5 antibodies on cell viability were measured using MTT assays and identification of morphological changes characteristic of apoptosis, after acridine orange staining. Sensitivity to the different death receptor ligands was stimulated using pretreatment with the cytokine IFN-gamma and the proteasome inhibitor MG-132. To investigate the mechanisms underlying the changes in rhTRAIL sensitivity, alterations in expression levels of targets of interest were measured by Western blot analysis. Co-immunoprecipitation was used to determine the composition of the death-inducing signalling complex at the cell membrane. RESULTS: SW948 cells were sensitive to all three of the DR-targeting agents tested, although the agonistic DR5 antibody induced only weak caspase 8 cleavage and limited apoptosis. Surprisingly, agonistic DR4 and DR5 antibodies induced equivalent DISC formation and caspase 8 cleavage at the level of their individual receptors, suggesting impairment of further caspase 8 processing upon DR5 stimulation. SW948-TR cells were cross-resistant to all DR-targeting agents as a result of decreased caspase 8 expression levels. Caspase 8 protein expression was restored by MG-132 and IFN-gamma pretreatment, which also re-established sensitivity to rhTRAIL and agonistic DR4 antibody in SW948-TR. Surprisingly, MG-132 but not IFN-gamma could also increase DR5-mediated apoptosis in SW948-TR. CONCLUSIONS: These results highlight a critical difference between DR4- and DR5-mediated apoptotic signaling modulation, with possible implications for future combinatorial regimens.


Assuntos
Carcinoma/patologia , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , Leupeptinas/farmacologia , Inibidores de Proteassoma , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
4.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34301808

RESUMO

BACKGROUND: Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab. METHODS: Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1). RESULTS: Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients. CONCLUSIONS: The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Antígeno B7-H1/imunologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Pró-Fármacos/administração & dosagem
5.
Lancet Oncol ; 10(4): 391-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19341970

RESUMO

Cardiovascular toxicity is one of the most devastating complications of cancer treatment and can arise during or shortly after treatment, or even several years later. Identification of the left ventricular ejection fraction (LVEF) is the most common method to screen for toxic effects on the heart; however, this approach underestimates cardiac damage and additional strategies for the monitoring of treatment-induced cardiotoxicity are being explored. Guidelines for monitoring have been formulated for several cancer treatments; however, appropriate underlying evidence is still largely absent. In this Review, we summarise conventional and contemporary methods for early detection of cardiotoxicity and designate a level of evidence for the basis of each method.


Assuntos
Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Coração/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Diagnóstico Precoce , Humanos
6.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32217763

RESUMO

BACKGROUND: Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging. METHODS: To study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974, 89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution. RESULTS: In tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes. CONCLUSION: [89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.


Assuntos
Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Complexo CD3/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Glipicanas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Tomografia por Emissão de Pósitrons/métodos , Animais , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Apoptose , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Radioisótopos/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Zircônio/química
7.
Theranostics ; 10(4): 1708-1718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042331

RESUMO

Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients' immune system, resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with 18F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy.


Assuntos
Biomarcadores Tumorais/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Biomarcadores Tumorais/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Seleção de Pacientes , Tomografia por Emissão de Pósitrons/métodos , Linfócitos T/imunologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos
10.
Eur J Cancer ; 50(2): 260-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24239447

RESUMO

PURPOSE: With the increasing use of novel targeted agents and the development of high imaging techniques, response evaluation criteria in solid tumour (RECIST) 1.1 developed primarily for cytotoxic agents and anatomic imaging, has demonstrated limitations. A survey was conducted of RECIST users to identify concerns and their suggestions for future RECIST criteria. METHODS: 140 key partners of the RECIST collaboration were asked to complete a questionnaire. The 49 questions concerned (a) satisfaction and concerns with RECIST 1.1; (b) use of modified RECIST criteria and (c) suggestions for the next RECIST Version. RESULTS: Sixty-five replies were received. 52.3% responders were satisfied with RECIST 1.1, while 10.8% indicated dissatisfaction. Areas of potential weakness included: (a) lack of incorporation of potential early indicators of response such as functional imaging, (b) lack of validation in rarer tumour types and (c) lack of validation for novel (targeted) agents. Suggestions were multiple, with highest numbers on two points: developing sub-criteria for certain disease types and including advanced imaging techniques for the evaluation. CONCLUSIONS: Constructive suggestions were received for optimising the next version. Ongoing data collection will make it possible to investigate the possible utilisation of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in tumour assessment, to verify whether RECIST is/can still be applicable in novel targeted therapy and to consider the need for criteria for specific disease types.


Assuntos
Neoplasias/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/normas , Guias de Prática Clínica como Assunto/normas , Inquéritos e Questionários , Fluordesoxiglucose F18 , Humanos , Neoplasias/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodos , Tomografia por Emissão de Pósitrons/métodos
11.
Cilia ; 2(1): 3, 2013 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-23384121

RESUMO

Pancreatic cysts are a heterogeneous group of lesions, which can be benign or malignant. Due to improved imaging techniques, physicians are more often confronted with pancreatic cysts. Little is known about the origin of pancreatic cysts in general. Von Hippel-Lindau (VHL) disease is an atypical ciliopathy and inherited tumor syndrome, caused by a mutation in the VHL tumor suppressor gene encoding the VHL protein (pVHL). VHL patients are prone to develop cysts and neuroendocrine tumors in the pancreas in addition to several other benign and malignant neoplasms. Remarkably, pancreatic cysts occur in approximately 70% of VHL patients, making it the only hereditary tumor syndrome with such a discernible expression of pancreatic cysts. Cellular loss of pVHL due to biallelic mutation can model pancreatic cystogenesis in other organisms, suggesting a causal relationship. Here, we give a comprehensive overview of various pVHL functions, focusing on those that can potentially explain pancreatic cyst development in VHL disease. Based on preclinical studies, cilia loss in ductal cells is probably an important early event in pancreatic cyst development.

12.
Hered Cancer Clin Pract ; 2(2): 99-105, 2004 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20233477

RESUMO

We report three Dutch families with familial clustering of (pre)neoplastic cervical disease, review the literature on familial risks of cervical intraepithelial neoplasia (CIN) and cervical cancer, and discuss possible practical guidelines for women with a family history of cervical cancer. Daughters and sisters of women with cervical cancer have been reported to have a relative risk of 1.5-2.3 to develop this type of cancer. From a practical clinical point of view, we suggest that as in women with an increased non-genetic risk to develop cervical cancer (e.g. because of immunosuppressive therapy) increased surveillance to detect this tumour should be considered in women with an increased risk based on family history. Cessation of smoking should be advised. As the use of condoms at least prevents HPV re-infection its use can be recommended as a way to lower the cervical cancer risk. Future studies to determine the genetic contribution to the development of cervical cancer should include the paternal family history of cancer and, because genetic predisposition might express itself as a higher risk to develop precursors of cervical cancer, carcinoma in situ and CIN grade II-III.

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