Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.861
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445615

RESUMO

Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. γδ T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation. Immunotherapy with activated γδ T cells is well tolerated; however, the clinical benefits are unsatisfactory. Therefore, the antitumor effects need to be increased. Administration of γδ T cells into local cavities might improve antitumor effects by increasing the effector-to-target cell ratio. Some anticancer and molecularly targeted agents increase the cytotoxicity of γδ T cells via mechanisms involving natural killer group 2 member D (NKG2D)-mediated recognition of target cells. Both the tumor microenvironment and cancer stem cells exert immunosuppressive effects via mechanisms that include inhibitory immune checkpoint molecules. Therefore, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors is a strategy that may improve cytotoxicity. The use of a bispecific antibody and chimeric antigen receptor might be effective to overcome current therapeutic limitations. Such strategies should be tested in a clinical research setting.


Assuntos
Citotoxicidade Imunológica/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445434

RESUMO

Human Cytomegalovirus (HCMV) infection is widespread and can result in severe sequelae in susceptible populations. Primary HCMV infection of naïve individuals results in life-long latency characterized by frequent and sporadic reactivations. HCMV infection elicits a robust antibody response, including neutralizing antibodies that can block the infection of susceptible cells in vitro and in vivo. Thus, antibody products and vaccines hold great promise for the prevention and treatment of HCMV, but to date, most attempts to demonstrate their safety and efficacy in clinical trials have been unsuccessful. In this review we summarize publicly available data on these products and highlight new developments and approaches that could assist in successful translation of HCMV immunotherapies.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Imunoterapia/métodos , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/uso terapêutico , Humanos
3.
Nutrients ; 13(7)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34371821

RESUMO

Food allergy (FA) is a pathological immune response, potentially deadly, induced by exposure to an innocuous and specific food allergen. To date, there is no specific treatment for FAs; thus, dietary avoidance and symptomatic medications represent the standard treatment for managing them. Recently, several therapeutic strategies for FAs, such as sublingual and epicutaneous immunotherapy and monoclonal antibodies, have shown long-term safety and benefits in clinical practice. This review summarizes the current evidence on changes in treating FA, focusing on monoclonal antibodies, which have recently provided encouraging data as therapeutic weapons modifying the disease course.


Assuntos
Alérgenos/imunologia , Anticorpos Monoclonais/uso terapêutico , Hipersensibilidade Alimentar/tratamento farmacológico , Hipersensibilidade Alimentar/imunologia , Imunoterapia/tendências , Anticorpos Monoclonais/imunologia , Humanos , Imunoterapia/métodos
4.
ACS Appl Mater Interfaces ; 13(33): 39003-39017, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433253

RESUMO

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.


Assuntos
Acetamidas/química , Aminopiridinas/química , Antineoplásicos/farmacologia , Benzamidas/química , Portadores de Fármacos/química , Inibidores de Checkpoint Imunológico/química , Piridinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Acetamidas/farmacologia , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Distribuição Tecidual , Resultado do Tratamento
5.
Biomolecules ; 11(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34356594

RESUMO

(1) Background: The interaction of the programmed death receptor (PD-1) with its ligand 1 (PD-L1) allows cancer cells to escape from the control of the immune system. Research evaluating the expression of immune checkpoint genes in the tissues of laryngeal tumors may contribute to the introduction of new effective immunotherapeutic methods in this group of neoplasms. The aim of this study was to evaluate the expression of the gene for the programmed death receptor (PD-1) and its ligand (PD-L1) in laryngeal tumors (T1, T2, T3) in patients without lymph node involvement and distant metastases. (2) Methods: The study included 73 patients: 39 of them were diagnosed with carcinoma planoepiteliale keratodes (study group) and 34 with nasal septal deviation undergoing septoplasty (control group). Biological material for molecular tests (Real time PCR) was collected during surgical procedures. Furthermore, all study participants completed a questionnaire regarding, among others, smoking and body weight. (3) Results: Gene expression for programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) was, statistically, significantly higher (p < 0.0001) in tumor tissue than in unchanged mucosa. Moreover, it was found that the greater the tumor size, the higher the expression level of the tested molecules. (4) Conclusions: Although further research on the role of the PD-1/PD-L1 pathway in laryngeal tumors is necessary, the presented reports are promising and may constitute a contribution to considerations on the introduction of targeted immunotherapy with anti-PD1 and anti-PD-L1 monoclonal antibodies in the treatment of these tumors.


Assuntos
Antígeno B7-H1/genética , Neoplasias Laríngeas/genética , Receptor de Morte Celular Programada 1/genética , Idoso , Anticorpos Monoclonais/genética , Antígeno B7-H1/metabolismo , Estudos de Coortes , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imunoterapia/métodos , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/fisiopatologia , Ligantes , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Morte Celular/genética , Receptores de Morte Celular/metabolismo , Transcriptoma/genética
6.
Front Immunol ; 12: 641206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367125

RESUMO

Endometriosis is a common, benign, and hormone-dependent gynaecological disorder that displays altered immunoinflammatory profiles. Myeloid-derived suppressor cells (MDSCs) suppressed immunosurveillance in endometriosis in human and mouse model. Receptor tyrosine kinase inhibitor Sunitinib can induce MDSC apoptosis and suppress the progression of cancer. However, the effects of Sunitinib on MDSCs in endometriosis and the underlying mechanism are not clear. In this study, we employed an animal study of the endometriosis model in mice for treatment of Sunitinib. After syngeneic endometrium transplantation and treatment, endometriotic lesion volume, weight, and histology were compared. Peritoneal fluid, peripheral blood, and bone marrow MDSC subsets and their molecular signaling were monitored by flow cytometry. Peritoneal cytokines were assayed by ELISA. The gene expression profiles of isolated CD11b+Ly6G+Ly6Clo cells were studied by RNA sequencing. We found that Sunitinib significantly decreased the endometriotic lesion size and weight after 1 and 3 weeks, and decreased p-STAT3 activation in MDSCs after 1 week of treatment. In the first week, Sunitinib specifically increased the G-MDSC population in peritoneal fluid but the isolated CD11b+Ly6G+Ly6Clo MDSCs after Sunitinib treatment were presented as mature polynuclear MDSCs, while the control group had immature mononuclear MDSCs. Importantly, we found Sunitinib differentially suppressed gene expressions of immunosuppressive function and differentiation in peritoneal G-MDSCs. Apelin signaling pathway associated genes and inflammation related genes were upregulated, and amino acid metabolism regulator genes were downregulated in bone marrow G-MDSCs. For endometriotic lesions, the PPARG gene governing glucose metabolism and fatty acid storage, which is important for the development of endometriosis was upregulated. In conclusion, Sunitinib inhibited endometriotic lesions, by promoting peritoneal fluid MDSCs maturation and inhibiting the immunosuppressive function. These findings suggest that Sunitinib changed the immune microenvironment and inhibited the development of endometriosis, which has potential therapeutic effects as novel immunotherapy to promote MDSCs maturation, differentiation, and metabolism for the treatment of endometriosis.


Assuntos
Endometriose/imunologia , Tolerância Imunológica/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Sunitinibe/farmacologia , Animais , Endometriose/patologia , Feminino , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Distribuição Aleatória
7.
J Immunol ; 207(5): 1468-1477, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34408009

RESUMO

Immuno-positron emission tomography (PET), a noninvasive imaging modality, can provide a dynamic approach for longitudinal assessment of cell populations of interest. Transformation of mAbs into single-chain variable fragment (scFv)-based PET imaging agents would allow noninvasive tracking in vivo of a wide range of possible targets. We used sortase-mediated enzymatic labeling in combination with PEGylation to develop an anti-mouse CD4 scFv-based PET imaging agent constructed from an anti-mouse CD4 mAb. This anti-CD4 scFv can monitor the in vivo distribution of CD4+ T cells by immuno-PET. We tracked CD4+ and CD8+ T cells in wild-type mice, in immunodeficient recipients reconstituted with monoclonal populations of OT-II and OT-I T cells, and in a B16 melanoma model. Anti-CD4 and -CD8 immuno-PET showed that the persistence of both CD4+ and CD8+ T cells transferred into immunodeficient mice improved when recipients were immunized with OVA in CFA. In tumor-bearing animals, infiltration of both CD4+ and CD8+ T cells increased as the tumor grew. The approach described in this study should be readily applicable to convert clinically useful Abs into the corresponding scFv PET imaging agents.


Assuntos
Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Monitorização Imunológica/métodos , Neoplasias Cutâneas/terapia , Animais , Anticorpos Monoclonais/metabolismo , Diagnóstico por Imagem , Feminino , Memória Imunológica , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons , Anticorpos de Cadeia Única/metabolismo
8.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
9.
J Immunol ; 207(5): 1298-1309, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34362833

RESUMO

Intralesional therapy is a promising approach for remodeling the immunosuppressive tumor microenvironment while minimizing systemic toxicities. A combinatorial in situ immunomodulation (ISIM) regimen with intratumoral administration of Fms-like tyrosine kinase 3 ligand (Flt3L), local irradiation, and TLR3/CD40 stimulation induces and activates conventional type 1 dendritic cells in the tumor microenvironment and elicits de novo adaptive T cell immunity in poorly T cell-inflamed tumors. However, the impact of ISIM on myeloid-derived suppressor cells (MDSCs), which may promote treatment resistance, remains unknown. In this study, we examined changes in the frequencies and heterogeneity of CD11b+Ly-6CloLy-6G+ polymorphonuclear (PMN)-MDSCs and CD11b+Ly-6ChiLy-6G- monocytic (M)-MDSCs in ISIM-treated tumors using mouse models of triple-negative breast cancer. We found that ISIM treatment decreased intratumoral PMN-MDSCs, but not M-MDSCs. Although the frequency of M-MDSCs remained unchanged, ISIM caused a substantial reduction of CX3CR1+ M-MDSCs that express F4/80. Importantly, these ISIM-induced changes in tumor-residing MDSCs were not observed in Batf3-/- mice. ISIM upregulated PD-L1 expression in both M-MDSCs and PMN-MDSCs and synergized with anti-PD-L1 therapy. Furthermore, ISIM increased the expression of IFN regulatory factor 8 (IRF8) in myeloid cells, a known negative regulator of MDSCs, indicating a potential mechanism by which ISIM decreases PMN-MDSC levels. Accordingly, ISIM-mediated reduction of PMN-MDSCs was not observed in mice with conditional deletion of IRF8 in myeloid cells. Altogether, these findings suggest that ISIM holds promise as a multimodal intralesional therapy to alter both lymphoid and myeloid compartments of highly aggressive poorly T cell-inflamed, myeloid-enriched tumors resistant to anti-PD-L1 therapy.


Assuntos
Células Dendríticas/imunologia , Imunoterapia/métodos , Fatores Reguladores de Interferon/metabolismo , Neoplasias Mamárias Animais/terapia , Proteínas de Membrana/uso terapêutico , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1 , Fatores de Transcrição de Zíper de Leucina Básica/genética , Antígenos CD40/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Resistência a Medicamentos , Regulação da Expressão Gênica , Humanos , Injeções Intralesionais , Fatores Reguladores de Interferon/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Radioterapia , Proteínas Repressoras/genética , Receptor 3 Toll-Like/metabolismo , Microambiente Tumoral
10.
Medicine (Baltimore) ; 100(32): e26138, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397868

RESUMO

RATIONALE: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options. Current treatments of ATC include surgery, radiation, and chemotherapy, used in combination when possible. In the aspect of immunotherapy, the biomarker of TMB-H and MSI-H may suggest that patients benefit from pembrolizumab. Programmed cell death-ligand 1 (PD-L1) is highly expressed in ATC but has not been written into the guidelines or approved by the FDA as a biomarker for thyroid cancer immunotherapy. PATIENT CONCERNS: A 55-year-old woman was admitted to our hospital because of a slight right-sided neck enlargement in November 2019. DIAGNOSES: The clinical diagnosis was ATC, pT3bN0M0, and stage IVB. INTERVENTIONS: Oral administration of apatinib (250 mg 3 times daily) was initiated after surgery, but some unpleasant side effects emerged after 1 month of treatment. Next-generation sequencing revealed that the tumor harbored 2 mutations, HRAS p.Q61R and TP53 p.P278S, and PD-L1 staining was positive with a high expression. Thus, camrelizumab (programmed cell death protein 1 inhibitor) was combined with apatinib, and apatinib was changed to 250 mg once a day from March 2020. OUTCOMES: No adverse reactions were observed after the treatment immunotherapy combined with antiangiogenic drugs. Currently, the survival time of patients is more than 11 months, and the quality of life is not affected. CONCLUSION: This case suggests that immunotherapy in patients with ATC based upon PD-L1 evaluation provides a therapeutic option. Targeting programmed cell death protein 1/PD-L1 may provide a much-needed treatment option for patients with advanced ATC.


Assuntos
Imunoterapia/métodos , Piridinas/administração & dosagem , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Administração Oral , Antineoplásicos/administração & dosagem , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Anaplásico da Tireoide/diagnóstico , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico
11.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
12.
Theranostics ; 11(16): 8057-8075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335980

RESUMO

Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer. At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients. In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy. Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner. The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management. In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy.


Assuntos
Imunoterapia/métodos , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/metabolismo , Humanos , Fatores Imunológicos , Neoplasias/imunologia , Neoplasias/terapia , Medicina de Precisão/métodos , Prognóstico
13.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361080

RESUMO

Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality, the effect of which is improved in combination with chemotherapy. PIT causes a super-enhanced permeability and retention (SUPR) effect. Here, we quantitatively evaluated the SUPR effect using radiolabeled drugs of varying molecular weights (18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808 nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both hindlimbs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were evaluated using positron emission tomography or single-photon emission computed tomography. Imaging studies found increased tumor accumulation of agents after PIT. PIT-treated tumors showed significantly increased uptake of 18F-5FU (p < 0.001) and 99mTc-HSA-D (p < 0.001). A tendency toward increased accumulation of 111In-DTPA and 111In-IgG was observed. These findings suggest that some low- and medium-molecular-weight agents are promising candidates for combined PIT, as are macromolecules; hence, administration after PIT could enhance their efficacy. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Sistemas de Liberação de Medicamentos , Imunoterapia/métodos , Neoplasias/terapia , Fototerapia/métodos , Cintilografia/métodos , Animais , Apoptose , Proliferação de Células , Terapia Combinada , Humanos , Verde de Indocianina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360566

RESUMO

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Hepáticas/imunologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia
15.
Theranostics ; 11(16): 7700-7714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335959

RESUMO

CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.


Assuntos
Imunoterapia/métodos , Células Th1/metabolismo , Irradiação Corporal Total/métodos , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Neoplasias , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Feminino , Imunidade/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Endogâmicos C3H , Imagem Óptica , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Células Th1/imunologia , Distribuição Tecidual
16.
Nat Commun ; 12(1): 4906, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385456

RESUMO

Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors exhibit superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offers better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherently aggressive biology including chemoresistance, likely mediated through progenitor-like gene expression and fibroblast activation. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a cancer cell population with an intriguing diametric response to major bladder cancer therapeutics. Importantly, it also provides a compelling framework for designing biomarker-guided clinical trials.


Assuntos
Caderinas/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cateninas/genética , Cateninas/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Estimativa de Kaplan-Meier , Terapia Neoadjuvante/métodos , Avaliação de Resultados em Cuidados de Saúde , Proteômica/métodos , RNA-Seq/métodos , Linfócitos T/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia
17.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203237

RESUMO

In the past decade, immunotherapies have been emerging as an effective way to treat cancer. Among several categories of immunotherapies, immune checkpoint inhibitors (ICIs) are the most well-known and widely used options for cancer treatment. Although several studies continue, this treatment option has yet to be developed into a precise application in the clinical setting. Recently, omics as a high-throughput technique for understanding the genome, transcriptome, proteome, and metabolome has revolutionized medical research and led to integrative interpretation to advance our understanding of biological systems. Advanced omics techniques, such as multi-omics, single-cell omics, and typical omics approaches, have been adopted to investigate various cancer immunotherapies. In this review, we highlight metabolomic studies regarding the development of ICIs involved in the discovery of targets or mechanisms of action and assessment of clinical outcomes, including drug response and resistance and propose biomarkers. Furthermore, we also discuss the genomics, proteomics, and advanced omics studies providing insights and comprehensive or novel approaches for ICI development. The overview of ICI studies suggests potential strategies for the development of other cancer immunotherapies using omics techniques in future studies.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Animais , Genômica/métodos , Humanos , Metabolômica/métodos , Microbiota/fisiologia , Proteômica/métodos
18.
Lancet Neurol ; 20(8): 639-652, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34302788

RESUMO

BACKGROUND: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe. METHODS: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 106 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 106 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783. FINDINGS: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months. INTERPRETATION: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients. FUNDING: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.


Assuntos
Vírus BK/imunologia , Imunoterapia/métodos , Leucoencefalopatia Multifocal Progressiva/terapia , Linfócitos T/imunologia , Adulto , Idoso , Doadores de Sangue , Estudos de Coortes , Determinação de Ponto Final , Estudos de Viabilidade , Feminino , Humanos , Imunoterapia/efeitos adversos , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Projetos Piloto , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299506

RESUMO

The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs' interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs' physicochemical properties-composition, shape, and size-determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs' interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy.


Assuntos
Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Nanopartículas/administração & dosagem , Ácidos Nucleicos/imunologia , Animais , Citocinas/imunologia , Humanos , Imunoterapia/métodos , Nanoestruturas/administração & dosagem
20.
Genes (Basel) ; 12(6)2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205689

RESUMO

Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson's disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53-87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD.


Assuntos
Anticorpos/uso terapêutico , Imunoterapia/métodos , Locomoção , Doença de Parkinson/terapia , alfa-Sinucleína/imunologia , Animais , Anticorpos/imunologia , Células CHO , Cricetinae , Cricetulus , Dependovirus/genética , Neurônios Dopaminérgicos/metabolismo , Vetores Genéticos/genética , Masculino , Doença de Parkinson/genética , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Ratos , Ratos Long-Evans , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , alfa-Sinucleína/química , alfa-Sinucleína/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...