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1.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988866

RESUMO

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Assuntos
Jejum , Neoplasias Renais/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Obesidade/complicações , Obesidade/genética
2.
Medicine (Baltimore) ; 99(37): e22153, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925773

RESUMO

BACKGROUND: Immune checkpoint blockade (ICB) brings hope to many late-stage cancer patients yet its marker for response remains elusive. METHODS: We developed a hypothesis that treatment-related adverse events (TrAEs) could predict objective response rate (ORR) to ICB. We plotted ORR against corresponding any and grade 3 to 5 (G3-5) TrAEs across a variety of cancer types by performing a meta-analysis using linear regression. RESULTS: We identified 113 eligible studies encompassing 25 types of malignancies that were treated with ICB or ICB-based regimes. A significant linear correlation was observed for any and severe TrAEs, respectively. The correlation coefficient was 0.57 (r = 0.324) for any TrAE and 0.61 (r = 0.37) for G3-5 TrAE. For melanoma, the correlation coefficient was 0.81 (r = 0.57) for any TrAE and 0.65 (r = 0.42) for G3-5 TrAEs. For RCC, the correlation coefficient was 0.86 (r = 0.74) for any TrAE and 0.91 (r = 0.83) for G3-5 TrAE. For NSCLC, the correlation coefficient was 0.55 (r = 0.3) for any TrAE and 0.74 (r = 0.86) for G3-5 TrAE. For UC, the correlation coefficient was 0.47 (r = 0.68) for any TrAE and 0.27 (r = 0.52) for G3-5 TrAE, yet the correlation was insignificant for severe AEs. CONCLUSION: Our findings suggest that over half of ICB responses could be reflected by any adverse events and ∼60% of responses could be reflected by severe AEs. Further validation is needed in individual trials.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Estadiamento de Neoplasias , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Análise de Sobrevida , Resultado do Tratamento
3.
Bull Cancer ; 107(7-8): 830-842, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32758364

RESUMO

Immune checkpoint inhibitors (ICI) have revolutionized oncological management in several tumor types, allowing prolonged tumoral responses. Thus, they are administered over long periods of time and can give specific autoimmune adverse reactions that may have a potential impact on quality of life (QoL). Most of phase III trials with ICI have included an assessment of QoL. In metastatic setting, in comparison with chemotherapy or targeted therapies, they indicate an absence of degradation of the QoL scores or even an improvement of these scores. In adjuvant setting, the deterioration of QoL scores is not clinically significant, regardless of the ICI used. In addition, there is no impairment of quality of life in patients with prolonged treatment duration. However, the measurement of QoL under ICI remains a challenge because of the specificities of these treatments and adapted measurement scales are being developed to improve the assessment of the impact of these treatments on patients' QoL.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Qualidade de Vida , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Inquéritos Epidemiológicos , Humanos , Imunoterapia Adotiva/efeitos adversos , Terapia de Alvo Molecular/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Int J Nanomedicine ; 15: 5279-5288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801691

RESUMO

Introduction: Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential. Methods: In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4. Results: Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio. Discussion: In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CTLA-4/imunologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Lipossomos/química , Camundongos Endogâmicos C57BL , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Linfócitos T Reguladores/efeitos dos fármacos
6.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32699182

RESUMO

Pneumonitis is a rare but serious adverse event caused by cancer immunotherapy. The diagnosis between COVID-19-induced pneumonia and immunotherapy-induced pneumonitis may be challenging in the era of COVID-19 outbreak. Some clinical symptoms and radiological findings of pneumonitis can be attributed to the coronavirus infection as well as to an immune-related adverse event. Identifying the exact cause of a pneumonitis in patients on treatment with immunotherapy is crucial to promptly start the most appropriate treatment. The proper management of immune checkpoint inhibitors for the risk of pneumonia must take into account a series of parameters. Accurate attention should be payed to symptoms like cough, fever and dyspnea during immunotherapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Infecções por Coronavirus/diagnóstico , Neoplasias/tratamento farmacológico , Pneumonia Viral/diagnóstico , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico , Betacoronavirus , Antígeno CTLA-4/antagonistas & inibidores , Técnicas de Laboratório Clínico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Diagnóstico Diferencial , Reações Falso-Negativas , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Pulmão/diagnóstico por imagem , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X
8.
Gene ; 754: 144888, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32544493

RESUMO

The development and progression of different pathologies including, cancer, are associated with suppressed immune responses. This restrained immune activity could be associated with the activation of different immune checkpoint pathways that mediate immunosuppressive functions. Therapeutic Protocols based on abolishing the activity of immune check points provided a promising potential for treating cancer. Among the distinct known immune checkpoints, PD-1/PD-L1 and CTLA-4, are the most studied and have been the focus for development of different blocking agents. Monoclonal antibodies that can block PD-1, PD-L1 or CTLA4 have been approved for treatment of different cancers. MicroRNAs (miRNAs), short non-coding regulatory RNA molecules, could repress mRNA expression at a post-transcriptional level. Many miRNAs have been reported to modulate the expression of CTLA-4 and PD-1/PD-L1, either directly or indirectly, in multiple pathological cases, mainly cancer. In this review, after a brief introduction about T cell activation and immune checkpoints, the miRNAs regulating the expression of CTLA-4 and PD-1/PD-L1 are discussed with highlights on their role in cancer. Many of these miRNAs could serve as novel treatments in different types of cancer as detailed throughout the review.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/métodos , Ativação Linfocitária , MicroRNAs/farmacologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia
9.
Cancer Treat Rev ; 88: 102057, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32574991

RESUMO

Despite advances in metastatic prostate cancer therapy, expected survival for patients in the castration-resistant phase of disease is poor. Immune-checkpoints inhibitors significantly prolonged life expectancy in some solid tumors and have been evaluated also in advanced stage prostate cancer. The majority of data available derive from preliminary phase I and II trials evaluating CTLA-4 and PD-1 as monotherapy or in combination with each other, vaccines, radiotherapy or targeted/hormonal therapy, achieving only limited benefits in terms of biochemical and radiologic responses. There are many reasons that may explain why prostate cancer responds poorly to modern immunotherapies, such as its characteristic low tumor mutational burden or immune-suppressive tumor microenvironment. The present review summarizes the results obtained treating advanced prostate cancer patients with immune-checkpoints inhibitors and analyzes potential mechanisms of both resistance and sensitivity, in order to hypothesize possible avenues of special interest for future research.


Assuntos
Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Clin Cancer Res ; 26(16): 4201-4205, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540850

RESUMO

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Neoplasias/tratamento farmacológico , Pneumonia Viral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Neoplasias/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
12.
Br J Cancer ; 123(5): 691-693, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546835
13.
Proc Natl Acad Sci U S A ; 117(24): 13428-13436, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32493746

RESUMO

The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.


Assuntos
Adjuvantes Imunológicos , Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Nanopartículas , Oligonucleotídeos/uso terapêutico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular , Sistemas de Liberação de Medicamentos , Quimioterapia Combinada , Inflamação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Nanopartículas/química , Neoplasias Experimentais/terapia , Oligonucleotídeos/química , Oligonucleotídeos/imunologia
14.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188384, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531324

RESUMO

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188385, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32554098

RESUMO

As a promising area of tumor treatment, immunotherapies, such as immune checkpoint inhibitors, have been applied to various types of cancer. However, many patients do not respond to such therapies. Increasing application of tumor ablation therapy, a minimally invasive treatment, has been observed in the clinic. Although it can boost the anti-tumor immune response of patients in many ways, ablation alone is not sufficient to remove the tumor completely or stop tumor recurrence in the long term. Currently, there is emerging research focusing on ablation in combination with immunotherapy, aiming to confirm the therapeutic value of this treatment for cancer patients. Hence, in this article, we review the classification, guideline recommendations, and immunomodulatory effects of ablation therapy, as well as the pre-clinical and clinical research of this combination therapy.


Assuntos
Técnicas de Ablação/métodos , Antineoplásicos Imunológicos/uso terapêutico , Hipertermia Induzida/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Técnicas de Ablação/normas , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Terapia Combinada/normas , Modelos Animais de Doenças , Humanos , Hipertermia Induzida/normas , Neoplasias/imunologia , Terapia Viral Oncolítica/normas , Vírus Oncolíticos/imunologia , Guias de Prática Clínica como Assunto , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
16.
Am Surg ; 86(4): 284-292, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391751

RESUMO

Progress in the arena of cancer immunotherapy has been immense in recent years. The fact remains that most of the cancer resections in the United States are performed by general surgeons and not oncologic specialists. A busy practice in general surgery will invariably make it difficult to keep pace with such rapid advancement. This review offers a concise summary of the major concepts and trials that have driven the immunotherapy revolution and their implications for surgeons who deliver cancer care.


Assuntos
Imunoterapia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Imunoterapia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia
17.
Nat Commun ; 11(1): 2168, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358520

RESUMO

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Ácidos Graxos Voláteis/sangue , Neoplasias/sangue , Neoplasias/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Biomarcadores Tumorais/metabolismo , Butiratos/sangue , Células Dendríticas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Ipilimumab/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Propionatos/sangue , RNA Ribossômico 16S/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
18.
Am J Kidney Dis ; 76(2): 299-302, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32417401
19.
Biomed Khim ; 66(2): 156-161, 2020 Feb.
Artigo em Russo | MEDLINE | ID: mdl-32420897

RESUMO

Current advances in research of immune checkpoints CTLA-4, PD-1, PD-L1, opened new possibilities for effective cancer immunotherapy using monoclonal antibodies. However, antibodies have a number of limitations for clinical use, which provides a basis for the search for low molecular weight compounds capable of regulating (blocking) molecules that inhibit the immune response. This paper presents the results of molecular docking and evaluation of synthetic peptide interaction with a CTLA-4 molecule. Using mathematical modeling, it was shown that peptides interacted with the 99MYPPPY104 loop of the CTLA-4 protein and could potentially block the interaction of the CTLA-4 receptor with its natural ligand B7-1. The specificity of the interaction between the identified peptide and recombinant chimeric CTLA-4 protein was evaluated. The detected synthetic peptide can be used for the development of immunomodulatory drugs for therapy of cancer or autoimmune diseases.


Assuntos
Antineoplásicos Imunológicos/química , Antígeno CTLA-4/antagonistas & inibidores , Peptídeos/química , Humanos , Imunoterapia , Simulação de Acoplamento Molecular
20.
PLoS One ; 15(4): e0231038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282861

RESUMO

OBJECTIVE: The aim of this study was to investigate if the treatment outcomes of checkpoint inhibitors (CPI) in patients with advanced-stage skin head and neck melanoma (HNM) differs from outcomes in patients with non-HNM. DESIGN: A retrospective cohort study of patients with unresectable AJCC stage III and stage IV, who received CPI between 2010 and 2017. PARTICIPANTS: Overall, 122 unresectable AJCC stage III and metastatic stage IV melanoma adult patients were treated with CPI during the study period (consecutive patients). The HNM group of patients was comparable with limbs and trunk melanoma group except different distant metastatic (M1a/b/c/d) pattern (p = 0.025). MAIN OUTCOMES: Comparison of overall survival and clinical response to CPI in patients with advanced-stage skin melanoma of the head and neck with non-HNM. RESULTS: We analyzed 38 patients with melanoma arising in the head and neck skin regions, 33 with melanoma of limbs and 51 with trunk melanoma. Most of the head and neck patients were men (89.5%), the average age of melanoma diagnosis was 61.4±16.7 years (range 16.4-85.6). More than a third of HNM group of patients (36.8%) were 70 years and older. Overall response rate (ORR) to CPI was 50% (CR 31.6% and PR 18.4%) in the head and neck study group of patients, compared to an ORR of 36.3% and 23.5% in melanoma of the limbs and of the trunk, respectively (p = 0.03). The median overall survival of HNM group of patients was 60.2±6.3 months, CI 95% [47.7-72.7], 63% were alive at 30 months, reaching a plateau. Whereas, the median survival time of limbs and trunk melanoma were 51.2 and 53.4 months, which did not reach significance. CONCLUSIONS AND RELEVANCE: Response rate to CPI is significantly improved in patients with melanoma of the head and neck and they have a trend towards improved, long standing, overall survival.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Ipilimumab/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias de Cabeça e Pescoço , Humanos , Masculino , Melanoma , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
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