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1.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
2.
N Engl J Med ; 383(12): 1149-1155, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32937047

RESUMO

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Plasmócitos/efeitos dos fármacos , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Creatinina/sangue , Creatinina/urina , Regulação para Baixo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Quimioterapia de Manutenção , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteinúria , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
3.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
4.
Nat Commun ; 11(1): 4051, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792548

RESUMO

The RNA genome of the human immunodeficiency virus (HIV) is reverse-transcribed into DNA and integrated into the host genome, resulting in latent infections that are difficult to clear. Here we show an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH), which includes viral reactivation, induction of cell death, inhibition of autophagy and the blocking of new infections. Viral reactivation triggers cell death specifically in HIV-1-infected T cells, which is promoted by agents that induce apoptosis and inhibit autophagy. SECH treatments can clear HIV-1 in >50% mice reconstituted with a human immune system, as demonstrated by the lack of viral rebound after withdrawal of treatments, and by adoptive transfer of treated lymphocytes into uninfected humanized mice. Moreover, SECH clears HIV-1 in blood samples from HIV-1-infected patients. Our results suggest a strategy to eradicate HIV infections by selectively eliminating host cells capable of producing HIV.


Assuntos
Infecções por HIV/prevenção & controle , HIV-1/patogenicidade , Animais , Antígenos CD34/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Azepinas/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Humanos , Camundongos , Organofosfatos/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Pirimidinonas/farmacologia , RNA Viral/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Triazóis/farmacologia
5.
PLoS Pathog ; 16(8): e1008679, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790802

RESUMO

Antiretroviral drugs that target various stages of the Human Immunodeficiency Virus (HIV) life cycle have been effective in curbing the AIDS epidemic. However, drug resistance, off-target effects of antiretroviral therapy (ART), and varying efficacy in prevention underscore the need to develop novel and alternative therapeutics. In this study, we investigated whether targeting the signaling molecule Sphingosine-1-phosphate (S1P) would inhibit HIV-1 infection and generation of the latent reservoir in primary CD4 T cells. We show that FTY720 (Fingolimod), an FDA-approved functional antagonist of S1P receptors, blocks cell-free and cell-to-cell transmission of HIV and consequently reduces detectable latent virus. Mechanistically, FTY720 impacts the HIV-1 life cycle at two levels. Firstly, FTY720 reduces the surface density of CD4, thereby inhibiting viral binding and fusion. Secondly, FTY720 decreases the phosphorylation of the innate HIV restriction factor SAMHD1 which is associated with reduced levels of total and integrated HIV, while reducing the expression of Cyclin D3. In conclusion, targeting the S1P pathway with FTY720 could be a novel strategy to inhibit HIV replication and reduce the seeding of the latent reservoir.


Assuntos
Cloridrato de Fingolimode/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/crescimento & desenvolvimento , Proteína 1 com Domínio SAM e Domínio HD/antagonistas & inibidores , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Linfócitos T/imunologia , Replicação Viral , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Lisofosfolipídeos/metabolismo , Fosforilação , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Linfócitos T/efeitos dos fármacos , Latência Viral
6.
Physiol Genomics ; 52(9): 401-407, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32809918

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1ß and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Perfilação da Expressão Gênica , Ocitocina/análogos & derivados , Pneumonia Viral/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Imunidade Adaptativa/genética , Betacoronavirus/imunologia , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Interações Hospedeiro-Patógeno , Humanos , Ocitocina/farmacologia , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Linfócitos T/imunologia , Linfócitos T/virologia , Transcriptoma
7.
PLoS One ; 15(7): e0236374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735564

RESUMO

We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.


Assuntos
Anticorpos Biespecíficos/farmacologia , Complexo CD3/imunologia , Receptores ErbB/imunologia , Glioma/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/imunologia , Complexo CD3/farmacologia , Modelos Animais de Doenças , Receptores ErbB/farmacologia , Feminino , Glioma/patologia , Glioma/terapia , Humanos , Imunoterapia/efeitos adversos , Masculino , Camundongos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
8.
Expert Opin Biol Ther ; 20(9): 1025-1031, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32700604

RESUMO

INTRODUCTION: The globally rampant SARS CoV-2 pandemic requires novel medical strategies to control the severity of disease and death due to complications. Of the 15-20% patients that develop pulmonary symptoms, a sub-set develops an acute respiratory distress syndrome (ARDS) rapidly progressing into a critical condition. Marked elevation of cytokines/chemokines is observed with elevation of additional markers of inflammation, coagulation, and organ damage such as CRP, D-dimer, LDH, Ferritin and Troponin-I. This hyperinflammation leads to worsening of oxygen saturation due to pulmonary infiltration and exudation, organ damage, and dysfunction of coagulation pathway and may lead to multi-organ failure. AREAS COVERED: The role of anti-inflammatory monoclonal antibodies such as Itolizumab, in cytokine storm. EXPERT OPINION: Itolizumab, an anti-CD6 humanized IgG1 mAb, binds to domain-1 of CD-6 that is responsible for priming, activation, and differentiation of T-cells. Itolizumab significantly reduces T-cell proliferation along with substantial downregulation of the production of cytokines/chemokines. Approved for moderate to severe chronic plaque psoriasis in 2013 it is currently being studied for addressing COVID-19 related cytokine storm and its complications. This article reviews its use in COVID-19 infections; its dose, administration protocol, contra-indications, and safety in treating moderate-to-severe ARDS by preventing and treating the cytokine storm and its complications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Pandemias , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
9.
PLoS One ; 15(7): e0235705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649682

RESUMO

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.


Assuntos
Antineoplásicos/farmacologia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Linfócitos T/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Interferons/farmacologia , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo
10.
Nat Commun ; 11(1): 3584, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681091

RESUMO

Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Imunoterapia , Linfócitos T/imunologia , Tamoxifeno/administração & dosagem , Vorinostat/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores Estrogênicos/imunologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
11.
Signal Transduct Target Ther ; 5(1): 89, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32533062

RESUMO

Coronavirus infections of multiple origins have spread to date worldwide, causing severe respiratory diseases. Seven coronaviruses that infect humans have been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. Among them, SARS-CoV and MERS-CoV caused outbreaks in 2002 and 2012, respectively. SARS-CoV-2 (COVID-19) is the most recently discovered. It has created a severe worldwide outbreak beginning in late 2019, leading to date to over 4 million cases globally. Viruses are genetically simple, yet highly diverse. However, the recent outbreaks of SARS-CoV and MERS-CoV, and the ongoing outbreak of SARS-CoV-2, indicate that there remains a long way to go to identify and develop specific therapeutic treatments. Only after gaining a better understanding of their pathogenic mechanisms can we minimize viral pandemics. This paper mainly focuses on SARS-CoV, MERS-CoV, and SARS-CoV-2. Here, recent studies are summarized and reviewed, with a focus on virus-host interactions, vaccine-based and drug-targeted therapies, and the development of new approaches for clinical diagnosis and treatment.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Terapia de Alvo Molecular/métodos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/genética , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
12.
Int J Nanomedicine ; 15: 3669-3680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547021

RESUMO

Introduction: The exhaustion and poor homing of activated lymphocytes are critical obstacles in adoptive cell immunotherapy for solid tumors. In order to effectively deliver immune cells into tumors, we encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor and utilized low-dose irradiation (LDI) as a tumoral attractor of T cells. Methods: Hydroxypropyl cellulose hydrogels were prepared by irradiation techniques, and the cross-sectional microstructure was characterized by scanning electron microscopy. The synergistic antitumor mechanism of combination of IFN-α2b and CIK cells was evaluated by detecting the expression of activation marker CD69 on CIK cell surface and IFN-γ production by CIK cells. The in vivo antitumor activity of IFN-α2b-incorporated hydroxypropyl cellulose hydrogels combined with CIK and radiation was evaluated in an MKN-45 xenografted nude mice model. Results: The bioactivity of IFN-α2b was well maintained in ultraviolet-reactive, rapidly cross-linkable hydroxypropyl cellulose hydrogels. In vitro studies demonstrated IFN-α2b-activated T cells, as evidenced by upregulating early activation marker CD69 and secretion inflammatory cytokine IFN-γ. In vivo real-time image showed our hydrogels kept a higher amount of drug delivery at the tumor site for a long time compared with free drug injection. Low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. Combination of IFN-α2b-loaded hydrogels (Gel-IFN) with T cells and LDI exhibited higher efficacy to eradicate human gastric cancer xenograted tumors with less proliferating cells and more necrotic regions compared with IFN-α2b or T cells alone. Discussion: HPC hydrogels kept the activity of IFN-α2b and stably release of IFN-α2b to stimulate T cells for a long time. At the same time, low-dose radiation recruits T cells into tumors. This innovative integration mode of IFN-α2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the therapeutic outcome of T cell therapy.


Assuntos
Antineoplásicos/uso terapêutico , Reagentes para Ligações Cruzadas/química , Hidrogéis/química , Interferon-alfa/uso terapêutico , Luz , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/radioterapia , Linfócitos T/imunologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Celulose/análogos & derivados , Celulose/química , Relação Dose-Resposta à Radiação , Elétrons , Humanos , Interferon-alfa/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Linfócitos T/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Cancer ; 135: 62-65, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32544799

RESUMO

While confirmed cases of the deadly coronavirus disease 2019 (COVID-19) have exceeded 4.7 million globally, scientists are pushing forward with efforts to develop vaccines and treatments in an attempt to slow the pandemic and lessen the disease's damage. Although no proven effective therapies for treating patients with COVID-19 or for managing their complications currently exist, the rapidly expanding knowledge regarding severe acute respiratory syndrome coronavirus 2 and its interplay with hosts provides a significant number of potential drug targets and the potential to repurpose drugs already tested in other diseases. Herein, we report the biological rationale of immune-activating drugs and a brief summary of literature data on the potential therapeutic value of immune checkpoint inhibitors that have been recently tested beyond cancer treatment for their potential to restore cellular immunocompetence.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Imunológicos/farmacologia , Linfopenia/sangue , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , Neoplasias/sangue , Neoplasias/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
14.
Leukemia ; 34(7): 1726-1729, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483300

RESUMO

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Células-Tronco Hematopoéticas/virologia , Inflamassomos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/prevenção & controle , Lesão Renal Aguda/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Furanos/farmacologia , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamassomos/genética , Miocardite/epidemiologia , Miocardite/imunologia , Miocardite/prevenção & controle , Miocardite/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Piroptose/genética , Piroptose/imunologia , Fatores de Risco , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
15.
PLoS One ; 15(6): e0234778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569289

RESUMO

Acute graft-versus-host-disease (GVHD), limits the use of hematopoietic cell transplant (HCT) to treat a variety of malignancies. Any new therapeutic approach must satisfy three requirements: 1) Prevent GVHD, 2) Maintain anti-pathogen immunity, and 3) Maintain anti-tumor immunity. In prior studies we have shown that the selective photosensitizer 2-Se-Cl eliminates highly alloreactive lymphocytes from the graft prior to HCT preventing GVHD and that antiviral immune responses were preserved following incubation with 2-Se-Cl. In this report, we investigated whether 2-Se-Cl treatment preserves antitumor immunity, and then used high dimensional flow cytometry to identify the determinants of successful immune reconstitution. Donor C57BL/6 splenocytes were cocultured for 4 days with irradiated BALB/c splenocytes and then exposed to 2-Se-Cl. Photodepletion (PD)-treated splenocytes were then infused into lethally irradiated BALB/c mice inoculated with A20 leukemia/lymphoma cells. Recipient mice that received PD-treated splenocytes survived > 100 days without evidence of GVHD or leukemia. In contrast, mice that did not receive PD-treated cells at time of HCT died of leukemia progression. Multiparameter flow cytometry of cytokines and surface markers on peripheral blood samples 15 days after HCT demonstrated unique patterns of immune reconstitution. We found that before clinical disease onset GVHD was marked by functionally exhausted T cells, while tumor clearance and long-term survival were associated with an expansion of polyfunctional T cells, monocytes, and DCs early after transplantation. Taken together these results demonstrate that 2-Se-Cl photodepletion is a new treatment that can facilitate HCT by preventing GVHD while preserving antiviral and anti-tumor immunity.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Fármacos Fotossensibilizantes/farmacologia , Compostos de Selênio/farmacologia , Animais , Antígeno CTLA-4/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Feminino , Leucemia/imunologia , Leucemia/terapia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
16.
Med Hypotheses ; 143: 109862, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32504923

RESUMO

COVID-19, a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread across the globe. Predisposing factors such as age, diabetes, cardiovascular disease, and lowered immune function increase the risk of disease severity. T cell exhaustion, high viral load, and high levels of TNF-ɑ, IL1ß, IL6, IL10 have been associated with severe SARS-CoV-2. Cytokine and antigen overstimulation are potentially responsible for poor humoral response to the virus. Lower cellular redox status, which leads to pro-inflammatory states mediated by TNF-ɑ is also potentially implicated. In vivo, in vitro, and human clinical trials have demonstrated N-acetylcysteine (NAC) as an effective method of improving redox status, especially when under oxidative stress. In human clinical trials, NAC has been used to replenish glutathione stores and increase the proliferative response of T cells. NAC has also been shown to inhibit the NLRP3 inflammasome pathway (IL1ß and IL18) in vitro, and decrease plasma TNF-ɑ in human clinical trials. Mediation of the viral load could occur through NAC's ability to increase cellular redox status via maximizing the rate limiting step of glutathione synthesis, and thereby potentially decreasing the effects of virally induced oxidative stress and cell death. We hypothesize that NAC could act as a potential therapeutic agent in the treatment of COVID-19 through a variety of potential mechanisms, including increasing glutathione, improving T cell response, and modulating inflammation. In this article, we present evidence to support the use of NAC as a potential therapeutic agent in the treatment of COVID-19.


Assuntos
Acetilcisteína/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Ensaios Clínicos como Assunto , Radicais Livres , Glutationa , Humanos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxirredução , Estresse Oxidativo , Pandemias , Síndrome Respiratória Aguda Grave , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
17.
Nat Cell Biol ; 22(7): 896-906, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541878

RESUMO

Tumour heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is known to affect the efficacy of cancer therapy, most personalized treatment approaches do not account for intratumour heterogeneity. We addressed this issue by studying the heterogeneity of nodal B-cell lymphomas by single-cell RNA-sequencing and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subpopulations and compared their drug-response and genomic profiles. Malignant subpopulations from the same patient responded strikingly differently to anti-cancer drugs ex vivo, which recapitulated subpopulation-specific drug sensitivity during in vivo treatment. Infiltrating T cells represented the majority of non-malignant cells, whose gene-expression signatures were similar across all donors, whereas the frequencies of T-cell subsets varied significantly between the donors. Our data provide insights into the heterogeneity of nodal B-cell lymphomas and highlight the relevance of intratumour heterogeneity for personalized cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/patologia , Linfócitos T/imunologia , Transcriptoma/efeitos dos fármacos , Microambiente Tumoral/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
18.
PLoS One ; 15(6): e0234965, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574193

RESUMO

There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.


Assuntos
Arsênico/toxicidade , Exposição Ambiental/efeitos adversos , Fumar/imunologia , Linfócitos T/efeitos dos fármacos , Vitamina D/sangue , Adulto , Idoso , Arsênico/urina , Bangladesh/epidemiologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fumar/sangue , Fumar/epidemiologia , Linfócitos T/imunologia , Vitamina D/imunologia
19.
Cancer Sci ; 111(9): 3132-3141, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579769

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD-L1 expression on tumors, tumor-infiltrating lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Mutação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
Leukemia ; 34(7): 1805-1815, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32518419

RESUMO

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Ensaios Clínicos como Assunto , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/enzimologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Esquema de Medicação , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Resultado do Tratamento
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