Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.059
Filtrar
1.
Front Immunol ; 11: 2059, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013871

RESUMO

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends."


Assuntos
Vacina BCG/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Celular , Imunidade Inata , Memória Imunológica/imunologia , Pneumonia Viral/imunologia , Vacinação , Idoso , Animais , Vacinas Anticâncer/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Micobactérias não Tuberculosas/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Risco , Vacinas Virais/efeitos adversos
2.
Front Immunol ; 11: 2059, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-798018

RESUMO

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends."


Assuntos
Vacina BCG/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Celular , Imunidade Inata , Memória Imunológica/imunologia , Pneumonia Viral/imunologia , Vacinação , Idoso , Animais , Vacinas Anticâncer/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Micobactérias não Tuberculosas/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Risco , Vacinas Virais/efeitos adversos
3.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
4.
Int J Nanomedicine ; 15: 5719-5743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821098

RESUMO

This review aims to summarize the methods that have been used till today, highlight methods that are currently being developed, and predict the future roadmap for anticancer therapy. In the beginning of this review, established approaches for anticancer therapy, such as conventional chemotherapy, hormonal therapy, monoclonal antibodies, and tyrosine kinase inhibitors are summarized. To counteract the side effects of conventional chemotherapy and to increase limited anticancer efficacy, nanodrug- and stem cell-based therapies have been introduced. However, current level of understanding and strategies of nanodrug and stem cell-based therapies have limitations that make them inadequate for clinical application. Subsequently, this manuscript reviews methods with fewer side effects compared to those of the methods mentioned above which are currently being investigated and are already being applied in the clinic. The newer strategies that are already being clinically applied include cancer immunotherapy, especially T cell-mediated therapy and immune checkpoint inhibitors, and strategies that are gaining attention include the manipulation of the tumor microenvironment or the activation of dendritic cells. Tumor-associated macrophage repolarization is another potential strategy for cancer immunotherapy, a method which activates macrophages to immunologically attack malignant cells. At the end of this review, we discuss combination therapies, which are the future of cancer treatment. Nanoparticle-based anticancer immunotherapies seem to be effective, in that they effectively use nanodrugs to elicit a greater immune response. The combination of these therapies with others, such as photothermal or tumor vaccine therapy, can result in a greater anticancer effect. Thus, the future of anticancer therapy aims to increase the effectiveness of therapy using various therapies in a synergistic combination rather than individually.


Assuntos
Antineoplásicos/farmacologia , Nanomedicina/tendências , Vacinas Anticâncer/imunologia , Humanos , Imunoterapia , Transplante de Células-Tronco , Microambiente Tumoral
5.
Nat Commun ; 11(1): 4225, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839463

RESUMO

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Chile , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Índia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , República da Coreia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
6.
Proc Natl Acad Sci U S A ; 117(33): 20159-20170, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747553

RESUMO

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6 -methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Vacinas Anticâncer/imunologia , Lactatos/metabolismo , Melanoma/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/fisiologia , Homólogo AlkB 5 da RNA Desmetilase/genética , Anticorpos , Citocinas/genética , Citocinas/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/terapia , Metiltransferases/genética , Metiltransferases/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Células Supressoras Mieloides/fisiologia , Sítios de Splice de RNA , Processamento de RNA , Simportadores/genética , Simportadores/metabolismo , Transcriptoma , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Anticancer Res ; 40(7): 3723-3732, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620611

RESUMO

BACKGROUND/AIM: Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. MATERIALS AND METHODS: Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. RESULTS: A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. CONCLUSION: BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.


Assuntos
Autofagia/fisiologia , Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Vacinas Anticâncer/imunologia , Feminino , Humanos , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia
8.
Proc Natl Acad Sci U S A ; 117(30): 17543-17550, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32669433

RESUMO

Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.


Assuntos
Antígenos de Neoplasias/imunologia , Imunomodulação , Ácidos Nucleicos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia , Camundongos , Oligodesoxirribonucleotídeos/imunologia , Oligonucleotídeos/imunologia , Oxirredução , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
10.
Nature ; 585(7823): 107-112, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728218

RESUMO

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Neoplásico/genética , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Linfócitos T/citologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Vacinação
11.
Internist (Berl) ; 61(7): 690-698, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32462251

RESUMO

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Melanoma/imunologia , Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Humanos , Melanoma/prevenção & controle , Neoplasias/prevenção & controle , Neoplasias/terapia , Linfócitos T/imunologia , Vacinação
12.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1055-G1069, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363891

RESUMO

Liver cancer is a worldwide disease, and, currently, due to the poor prognostic and therapeutic options of liver cancer, we investigated the T cell epitopes as potential therapeutic vaccine candidates to get the benefit of experimental processes and utilize the complete ability of the immune system compared with other artificial ex vivo proliferation of T cells. Activation of T cells targets and kills several tumors, developing a strong rationale for the improvement of immunotherapeutic strategies to cancer therapy. To predict T cell epitopes for liver cancer, we designed a comprehensive immunoinformatics framework involving data mining, immunogenicity prediction, functional proteomic analysis, conservation studies, molecular modeling, and in vivo validation analysis. We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) I molecules to control the cancerous activity. Five extracellular antigenic proteins, including complement protein (C6), serotransferrin, coagulation factor XIII B, serum albumin (ALB), and prothrombin, were identified. We predicted and synthesized T cell epitopes to human leukocytes antigen-A*01:01 allele of MHC class I molecule. The hematological assay and IgG ELISA showed that C6 and ALB epitopes induced the production of lymphocytes, granulocytes, and peptide-specific IgG in immunized rats. We observed substantial high levels of granzymes B in serum samples of C6 and ALB compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.NEW & NOTEWORTHY We observed substantial high levels of granzymes B in serum samples of component C6 (C6) and albumin (ALB) compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Neoplasias Hepáticas/prevenção & controle , Proteínas de Neoplasias/imunologia , Animais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Proteômica , Ratos
13.
Cancer Immunol Immunother ; 69(10): 2001-2007, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32393999

RESUMO

Cancer immunotherapy including vaccine therapy is a promising modality for cancer treatment, but few patients show its clinical benefits currently. The identification of biomarkers that can identify patients who will benefit from cancer immunotherapy is thus important. Here, we investigated the potential utility of the circulating cell-free DNA (cfDNA) integrity-a ratio of necrotic cell-derived, longer DNA fragments versus apoptotic cell-derived shorter fragments of Alu gene-as a biomarker of vaccine therapy for patients with ovarian cancer. We analyzed plasma samples from 39 patients with advanced or recurrent ovarian cancer enrolled in clinical trials for personalized peptide vaccinations. We observed that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the decreased levels of cfDNA integrity were correlated with vaccine-induced immune responses; i.e., decreased cfDNA integrity was observed in 91.7% and 59.3% of the IgG-positive and negative patients, respectively (p = 0.0445). Similarly, decreased cfDNA integrity was observed in 92.9% and 56.0% of CTL response-positive and negative patients, respectively (p = 0.0283). These results suggest that the circulating cfDNA integrity is a possible biomarker for cancer vaccine therapy.


Assuntos
Biomarcadores Tumorais/imunologia , Vacinas Anticâncer/imunologia , Carcinoma Epitelial do Ovário/imunologia , DNA Tumoral Circulante/sangue , Recidiva Local de Neoplasia/imunologia , Neoplasias Ovarianas/imunologia , Vacinas de Subunidades/imunologia , Vacinas Anticâncer/administração & dosagem , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/genética , DNA Tumoral Circulante/genética , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Prognóstico , Vacinas de Subunidades/administração & dosagem
14.
Prostate ; 80(11): 811-823, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32427375

RESUMO

BACKGROUND: Exosomes secreted by tumor cells can be regarded as carriers of tumor-associated antigens and have potential value in tumor immunotherapy. The aim of this study was to evaluate the antitumor efficacy of a novel exosomal vaccine (interferon-γ [IFN-γ]-modified exosomal vaccine) in prostate cancer. METHODS: Prostate cancer cell-derived exosomes were used to prepare the exosomal vaccine using our protein-anchoring technique. The immunogenicity and therapeutic efficacy of the exosomes was evaluated by measuring the effects of the exosomal vaccine on M1 macrophage differentiation, the ability of macrophages to engulf the exosomes, the production of antibodies against exosomes, and tumor angiogenesis and metastasis, and tumor growth. RESULTS: The IFN-γ fusion protein was efficiently anchored on the surface of prostate cancer cell-derived exosomes and retained its bioactivity. The IFN-γ-exosomal vaccine increased the number of M1 macrophages, enhanced the ability of M1 macrophages to engulf RM-1 cell-derived exosomes, and induced the production of specific antibodies against exosomes. The exosomal vaccine downregulated the expression of vascular endothelial growth factor receptor 2 and attenuated the effect of exosomes in promoting tumor metastasis. The proportions of CD4+ , CD8+ , and IFN-γ+ CD8+ T cells in the exosomal vaccine group were the highest among the four groups. Interestingly, the IFN-γ-exosomal vaccine decreased the percentage of Tregs and downregulated the expression of programed death-ligand 1 and indoleamine 2, 3-dioxygenase 1 in the tumor environment. The exosomal vaccine significantly inhibited tumor growth and prolonged the survival time of mice with prostate cancer. The exosomal and tumor cell vaccines had a good synergistic effect in promoting tumor immunity. CONCLUSIONS: The novel exosomal vaccine induced an immune response that cleared prostate cancer cell-derived exosomes, thereby eliminating the regulatory effect of the exosomes. This study may provide experimental evidence for the use of exosomes as a therapeutic tool or target in immunotherapy for human prostate cancer.


Assuntos
Vacinas Anticâncer/farmacologia , Exossomos/imunologia , Interferon gama/farmacologia , Neoplasias da Próstata/terapia , Animais , Anticorpos Antineoplásicos/biossíntese , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Vacinas Anticâncer/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Citocinas/sangue , Citocinas/imunologia , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/imunologia , Distribuição Aleatória , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
15.
Life Sci ; 252: 117646, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272178

RESUMO

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells causing resistance to immunotherapies in cancer tumors. In the current study, various immunogenic and therapeutic features of the combination therapies with non-liposomal Doxorubicin (Dox) and the E75 immunogenic peptide (Pep), derived from the human epidermal receptor-2 (HER-2), are investigated in parallel with their liposomal formulations (Lip-Dox (Doxil®) and Lip-Pep). Therefore, triple injection doses of Lip-Pep were preceded with Dox and Lip-Dox injections in TUBO/breast tumor-bearing BALB/c mice. Chemotherapy with either Dox or Lip-Dox reduced the frequency of MDSCs, the level of reactive oxygen species (ROS), and MDSCs-associated genes of Arg1, iNOS, S100A8, S100A9. Whereas Lip-Pep + Dox and Lip-Pep + Lip-Dox treatments synergistically potentiated the immunized splenocytes to produce INF-γ and enhanced the frequency of the anti-tumor CD8+ and CD4+ T cells as opposed to both chemotherapy and immunotherapy regimens. Chemo-immunotherapy increased the number of tumor-infiltrating lymphocytes (TILs) and reduced the level of CD25+ FoxP3+ T regulatory cells. Taken together, chemo-immunotherapy was the optimum treatment for the limitation of tumor progression as they targeted more cancer-related immune players.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Doxorrubicina/análogos & derivados , Receptor ErbB-2/imunologia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Terapia Combinada , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Feminino , Imunoterapia/métodos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia
16.
Int J Nanomedicine ; 15: 1983-1996, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308382

RESUMO

Background: Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms. Purpose: This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses. Methods: A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to virus-like particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model. Results: Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8+ IFN-γ+ cytotoxic T lymphocytes (CTLs) and CD4+ IFN-γ+ Th1 cells were significantly increased, whereas the immunosuppressive cells CD4+ CD25+ FOXP3+ Treg cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses. Conclusion: Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.


Assuntos
Vacinas Anticâncer/farmacologia , Epitopos de Linfócito B/imunologia , Fator 2 de Crescimento de Fibroblastos/imunologia , Peptídeos/imunologia , Vacinas de Partículas Semelhantes a Vírus/farmacologia , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunoterapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Neovascularização Patológica/tratamento farmacológico , Peptídeos/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Vacinação , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/imunologia
17.
Nat Commun ; 11(1): 1985, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332752

RESUMO

The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Nanopartículas/administração & dosagem , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Humanos , Imunidade Inata/genética , Camundongos , Recidiva Local de Neoplasia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Intervalo Livre de Progressão , RNA Interferente Pequeno/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
18.
Nat Biotechnol ; 38(6): 715-721, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32231335

RESUMO

Mining the antibody repertoire of plasma cells and plasmablasts could enable the discovery of useful antibodies for therapeutic or research purposes1. We present a method for high-throughput, single-cell screening of IgG-secreting primary cells to characterize antibody binding to soluble and membrane-bound antigens. CelliGO is a droplet microfluidics system that combines high-throughput screening for IgG activity, using fluorescence-based in-droplet single-cell bioassays2, with sequencing of paired antibody V genes, using in-droplet single-cell barcoded reverse transcription. We analyzed IgG repertoire diversity, clonal expansion and somatic hypermutation in cells from mice immunized with a vaccine target, a multifunctional enzyme or a membrane-bound cancer target. Immunization with these antigens yielded 100-1,000 IgG sequences per mouse. We generated 77 recombinant antibodies from the identified sequences and found that 93% recognized the soluble antigen and 14% the membrane antigen. The platform also allowed recovery of ~450-900 IgG sequences from ~2,200 IgG-secreting activated human memory B cells, activated ex vivo, demonstrating its versatility.


Assuntos
Anticorpos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas Analíticas Microfluídicas/instrumentação , Análise de Célula Única , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , DNA/análise , DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunoglobulina G/genética , Camundongos , Análise de Célula Única/instrumentação , Análise de Célula Única/métodos
19.
ESMO Open ; 4(Suppl 3)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32269031

RESUMO

The success of cancer therapies with immune checkpoint inhibitors is transforming the treatment of patients with cancer and fostering cancer research. Therapies that target immune checkpoint inhibitors have shown unprecedented rates of durable long-lasting responses in patients with various cancer types, but only in a fraction of patients. Thus, novel approaches are needed to make immunotherapy more precise and also less toxic. The advances of next-generation sequencing technologies have allowed fast detection of somatic mutations in genes present in the exome of an individual tumour. Targeting neoantigens, the mutated peptides expressed only by tumour cells, may enable antitumour T-cell responses and tumour destruction without causing harm to healthy tissues. Currently, neoantigens can be identified in tumour clinical samples by using genomic-based computational tools. The two main treatment modalities targeting neoantigens that have been investigated in clinical trials are personalised vaccines and tumour infiltrating lymphocytes-based adoptive T-cell therapy. In this mini review, we discuss the promises and challenges for using neoantigens as emergent targets to personalise and guide cancer immunotherapy in a broader set of cancers.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Humanos , Imunoterapia Adotiva , Terapia de Alvo Molecular , Neoplasias/imunologia
20.
Nat Commun ; 11(1): 1110, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111828

RESUMO

Targeted delivery of a nanovaccine loaded with a tumor antigen and adjuvant to the lymph nodes (LNs) is an attractive approach for improving cancer immunotherapy outcomes. However, the application of this technique is restricted by the paucity of suitable tumor-associated antigens (TAAs) and the sophisticated technology required to identify tumor neoantigens. Here, we demonstrate that a self-assembling melittin-lipid nanoparticle (α-melittin-NP) that is not loaded with extra tumor antigens promotes whole tumor antigen release in situ and results in the activation of antigen-presenting cells (APCs) in LNs. Compared with free melittin, α-melittin-NPs markedly enhance LN accumulation and activation of APCs, leading to a 3.6-fold increase in antigen-specific CD8+ T cell responses. Furthermore, in a bilateral flank B16F10 tumor model, primary and distant tumor growth are significantly inhibited by α-melittin-NPs, with an inhibition rate of 95% and 92%, respectively. Thus, α-melittin-NPs induce a systemic anti-tumor response serving as an effective LN-targeted whole-cell nanovaccine.


Assuntos
Vacinas Anticâncer/imunologia , Sistemas de Liberação de Medicamentos , Linfonodos/imunologia , Meliteno/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Vacinas Anticâncer/metabolismo , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Imunoterapia , Lipídeos/administração & dosagem , Lipídeos/química , Linfonodos/metabolismo , Meliteno/química , Meliteno/imunologia , Meliteno/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/terapia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA