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1.
Anticancer Res ; 41(3): 1485-1496, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788741

RESUMO

BACKGROUND: As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A. PATIENTS AND METHODS: Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met. RESULTS: Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival. CONCLUSION: The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Vacinas Anticâncer/administração & dosagem , Cinesina/antagonistas & inibidores , Vacinas de Subunidades/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/imunologia , Neoplasias do Sistema Biliar/metabolismo , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Feminino , Febre/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Cinesina/imunologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Prognóstico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia
2.
J Immunother ; 43(4): 121-133, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31834207

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor ß1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.


Assuntos
Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Receptor Patched-1/metabolismo , Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Comunicação Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibrose , Humanos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Receptor Patched-1/química , Receptor Patched-1/genética , Peptídeos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 38(11): 6121-6126, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30396927

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of cancer-related death. FOLFOX, a combination of leucovorin calcium, fluorouracil, and oxaliplatin, is the first-line chemotherapy for stage III and stage IV CRC. However, patients with FOLFOX-resistant CRC have a poor prognosis. In recent years, virochemotherapy has been proposed as a potential treatment for chemotherapy-resistant cancer. MATERIALS AND METHODS: Through our first screening assay, we found that coxsackievirus A11 (CVA11) displayed potent oncolytic activities. We tested whether coxsackievirus A11 (CVA11) has oncolytic activity in human CRC cells in vitro and in vivo. We also examined whether pretreatment of oxaliplatin-resistant CRC cells with oxaliplatin enhances the oncolytic activity of CVA11. RESULTS: We found that CVA11 was potently oncolytic against the oxaliplatin-sensitive Caco-2 cell line, but had little effect on the oxaliplatin-resistant line WiDr. However, pretreatment of WiDr cells with oxaliplatin enhanced the oncolytic activity of CVA11, and the combination therapy was more cytotoxic than either oxaliplatin treatment or CVA11 infection alone. Furthermore, growth of subcutaneous WiDr tumors in a xenograft model was significantly lower in mice treated with oxaliplatin followed by intratumoral CVA11 injection compared with mice receiving either treatment alone. CONCLUSION: Oxaliplatin pretreatment sensitized oxaliplatin-resistant CRC cells to lysis by CVA11 infection in vitro and in vivo. Taken together, these findings identify a novel potential chemovirotherapeutic modality for the treatment of oxaliplatin-resistant human CRC.


Assuntos
Neoplasias Colorretais/terapia , Enterovirus/fisiologia , Terapia Viral Oncolítica/métodos , Oxaliplatina/farmacologia , Animais , Antígenos CD55/biossíntese , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/virologia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Enterovirus/efeitos dos fármacos , Feminino , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 38(8): 4543-4547, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061220

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) is still a deadly type of cancer for which there are few effective therapeutic strategies. Development of a new molecule targeting agent is urgently desired. Previously we showed that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) are new therapeutic targets for pancreatic cancer. In the present study, we analyzed whether RBPJ/MAML3 inhibition could also be a new therapeutic strategy for SCLC. MATERIALS AND METHODS: Using silencing of RBPJ/MAML3, proliferation, invasion, migration and chemosensitivity of SBC-5 cells were investigated. RESULTS: RBPJ/MAML3 inhibition reduced Smoothened and HES1 expression, suggesting that RBPJ/MAML3 signaling was through Hedgehog and NOTCH pathways. In the analysis of cell functions, RBPJ/MAML3 inhibition significantly reduced proliferation and invasiveness via reduction of expression of matrix metalloproteinases. On the other hand, RBPJ/MAML3 inhibition also reduced chemosensitivity to cis-diamminedichlo-roplatinum and gemcitabine. CONCLUSION: These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Transativadores
5.
Cancer Immunol Res ; 6(4): 378-388, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475880

RESUMO

T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single-T-cell analysis protocol that allows the rapid capture of paired TCRα and ß cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TIL) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50% to 70% of CD137+CD8+ TILs, indicating that they responded to certain antigens in the tumor environment. To assess the tumor reactivity of the TCRs derived from those clonally expanded TILs in detail, we then analyzed the CD137+CD8+ TILs from the tumor of B16F10 melanoma cells in six C57BL/6 mice and analyzed their TCR repertoire. We also found clonally expanded T cells in 60% to 90% of CD137+CD8+ TILs. When the tumor reactivity of dominant clonotypic TCRs in each mouse was analyzed, 9 of 13 TCRs induced the secretion of IFNγ in response to, and showed killing of, B16F10 cells in vitro, and 2 of them showed strong antitumor activity in vivo Concerning their antigen specificity, 7 of them reacted to p15E peptide of endogenous murine leukemia virus-derived envelope glycoprotein 70, and the rest reacted to tumor-associated antigens expressed on EL4 lymphoma as well as B16 melanoma cells. These results show that our strategy enables us to simply and rapidly obtain the tumor-specific TCR repertoire with high fidelity in an antigen- and MHC haplotype-independent manner from primary TILs. Cancer Immunol Res; 6(4); 378-88. ©2018 AACR.


Assuntos
Transformação Celular Neoplásica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Melanoma Experimental , Camundongos , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única/métodos , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transdução Genética
6.
PLoS One ; 13(1): e0187878, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293510

RESUMO

The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Ciclofosfamida/uso terapêutico , Proteínas de Ligação a DNA/química , Imunoterapia , Neoplasias/terapia , Proteínas Oncogênicas/química , Peptídeos/uso terapêutico , Adulto , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Peptídeos/efeitos adversos , Reação em Cadeia da Polimerase em Tempo Real , Ubiquitina-Proteína Ligases
7.
Clin Immunol ; 166-167: 48-58, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27072896

RESUMO

We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/imunologia , Ciclofosfamida/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Vacinas de Subunidades/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Epitopos/administração & dosagem , Epitopos/imunologia , Feminino , Antígeno HLA-A24/genética , Antígeno HLA-A24/imunologia , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Peptídeos/administração & dosagem , Peptídeos/imunologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos
8.
Int J Hematol ; 102(4): 493-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25995001

RESUMO

A 57-year-old male with acute-type adult T cell leukemia-lymphoma (ATL) developed persistent watery, non-bloody diarrhea at a volume of 2-3 L/day following the administration of the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. An extensive examination revealed the absence of any pathogenic bacteria or parasites in his stool. Biopsied specimens from the colonic mucosa contained many small nests of apoptotic bodies in the colonic glands, which mimicked acute-colonic graft-versus-host disease. Activation of the auto-reactive immune system due to the depletion of regulatory T-cells by mogamulizumab was suspected as causative. Special attention should be paid to the risk of unique immune-related adverse events induced by mogamulizumab.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Colite , Doença Enxerto-Hospedeiro , Receptores CCR4/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Colite/induzido quimicamente , Colite/diagnóstico , Doença Enxerto-Hospedeiro/induzido quimicamente , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia
9.
Blood ; 120(17): 3444-54, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22936657

RESUMO

BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4(+) T subsets and increasing numbers of Th17 and memory CD44(hi)CD4(+) T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4(+) T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF-induced antitumor memory CD4(+) T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Leucemia Experimental/imunologia , Receptores do Leucotrieno B4/imunologia , Transdução de Sinais/imunologia , Imunidade Adaptativa , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Imunidade Inata , Memória Imunológica , Leucemia Experimental/genética , Leucemia Experimental/patologia , Leucotrieno B4/imunologia , Leucotrieno B4/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Knockout , Receptores do Leucotrieno B4/deficiência , Receptores do Leucotrieno B4/genética , Transdução de Sinais/genética , Transdução Genética
11.
Intern Med ; 49(20): 2247-52, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20962444

RESUMO

We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin.


Assuntos
Infarto Cerebral/etiologia , Doença de Fabry/complicações , Inflamação/etiologia , Adulto , Biomarcadores , Proteína C-Reativa/análise , Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Febre/etiologia , Humanos , Inflamação/sangue , Masculino , Mutação de Sentido Incorreto , Proteínas Recombinantes/uso terapêutico , Recidiva , Oclusão da Artéria Retiniana/etiologia , Doenças Retinianas/etiologia , Adulto Jovem , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêutico
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