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1.
Cancer Immunol Immunother ; 64(6): 707-16, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25772149

RESUMO

To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks from the first administration of maintenance temozolomide. All patients showed good tolerability during the observation period. Skin disorders, such as grade 1/2 injection-site reactions, were observed in all seven patients. Although grade 3 lymphocytopenia potentially due to concurrent radio/temozolomide therapy was observed in five patients (71.4 %), no other grade 3/4 hematological or neurological toxicities were observed. No autoimmune reactions were observed. All patients are still alive, and six are on Wilms tumor 1 peptide vaccination without progression, yielding a progression-free survival from histological diagnosis of 5.2-49.1 months. Wilms tumor 1 peptide vaccination was stopped in one patient after 12 injections by the patient's request. The safety profile of the combined Wilms tumor 1 peptide vaccination and temozolomide therapy approach for treating glioblastoma was confirmed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Proteínas WT1/administração & dosagem , Proteínas WT1/imunologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Estudos de Coortes , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Progressão da Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Proteínas WT1/efeitos adversos
2.
J Cancer Res Clin Oncol ; 139(3): 457-63, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23160854

RESUMO

OBJECTIVE: The aim of the present study was to analyze the long-term survival effects of WT1 peptide vaccine, in addition to its anti-tumor effects and toxicity. METHODS: A phase II clinical trial was conducted during the period of 2004-2010 at Osaka University Hospital, Osaka, Japan. The patients who had gynecologic malignancies progressing against previous treatments received WT1 peptide vaccine intradermally at 1-week intervals for 12 weeks. The vaccination was allowed to further continue, unless the patient's condition became significantly worse due to the disease progression. RESULTS: Forty out of 42 patients, who met all the inclusion criteria, underwent WT1 peptide vaccine. Among these 40 patients, stable disease was observed in 16 cases (40 %). Skin toxicity of a grade 1, 2 and 3 occurred in 25 cases (63 %), 9 cases (23 %) and a single case (3 %), respectively, and liver toxicity of grade 1 in a single case (3 %). The overall survival period was significantly longer in cases positive for the WT1 peptide-specific delayed-type hypersensitivity (DTH) reaction after the vaccination, compared to those negative for the DTH reaction (p = 0.023). Multivariate Cox proportional hazards analysis demonstrated that the adjusted hazard ratio for the negative DTH reaction was 2.73 (95 % CI 1.04-7.19, p = 0.043). CONCLUSION: WT1 peptide vaccine may be a potential treatment, with limited toxicity, for gynecologic malignancies that have become resistant to conventional therapies. Larger scale of clinical studies is required to establish the efficacy of the WT1 peptide vaccine for gynecologic malignancies.


Assuntos
Carcinoma/terapia , Neoplasias dos Genitais Femininos/terapia , Oligopeptídeos/uso terapêutico , Proteínas WT1/uso terapêutico , Adulto , Idoso , Carcinoma/mortalidade , Carcinoma/patologia , Progressão da Doença , Feminino , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias dos Genitais Femininos/patologia , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Terapia de Salvação , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento , Proteínas WT1/efeitos adversos
3.
Anticancer Res ; 32(6): 2263-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22641661

RESUMO

BACKGROUND: The aim of this study was to investigate the safety and efficacy of combinatorial use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and CpG oligodeoxynucleotides (CpG-ODN) as immunoenhancement adjuvants in Wilms' Tumor 1 (WT1) vaccine therapy for patients with solid malignancy. PATIENTS AND METHODS: The patients were placed into treatment groups as follows: WT1 peptide alone, WT1 peptide with GM-CSF (100 µg) and WT1 peptide with CpG-ODN (100 µg). HLA-A *2402 or *0201/*0206-restricted, WT1 peptide emulsified with Montanide ISA51 was injected intradermally every week for eight weeks. Toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 3.0. Tumor size, which was measured by computed tomography, was determined every four weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors. RESULTS: The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The disease control rate of the groups treated with WT1 peptide alone (n=10), with combinatorial use of GM-CSF (n=8) and with combinatorial use of CpG-ODN (n=10), in the initial two months was 20%, 25% and 60%, respectively. CONCLUSION: Addition of GM-CSF or CpG-ODN to the WT1 peptide vaccine for patients with solid malignancy was safe and improved the effectiveness of clinical response.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Ilhas de CpG , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Neoplasias/terapia , Oligonucleotídeos/administração & dosagem , Proteínas WT1/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Idoso , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Ilhas de CpG/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imuno-Histoquímica , Masculino , Manitol/administração & dosagem , Manitol/efeitos adversos , Manitol/análogos & derivados , Manitol/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/efeitos adversos , Ácidos Oleicos/imunologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Proteínas WT1/efeitos adversos , Proteínas WT1/imunologia
4.
Cancer Immunol Immunother ; 60(2): 161-71, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20963411

RESUMO

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Leucemia Mieloide Aguda/terapia , Manitol/análogos & derivados , Mieloma Múltiplo/terapia , Ácidos Oleicos , Oligodesoxirribonucleotídeos , Peptídeos/uso terapêutico , Adolescente , Antígenos de Neoplasias/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Feminino , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Masculino , Manitol/efeitos adversos , Mucina-1/efeitos adversos , Mucina-1/química , Mucina-1/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloblastina/efeitos adversos , Mieloblastina/química , Mieloblastina/imunologia , Estadiamento de Neoplasias , Neoplasia Residual/imunologia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Ácidos Oleicos/efeitos adversos , Oligodesoxirribonucleotídeos/efeitos adversos , Oligodesoxirribonucleotídeos/imunologia , Peptídeos/efeitos adversos , Peptídeos/imunologia , Projetos Piloto , Resultado do Tratamento , Proteínas WT1/efeitos adversos , Proteínas WT1/química , Proteínas WT1/imunologia
6.
Blood ; 113(26): 6541-8, 2009 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-19389880

RESUMO

This study investigated the immunogenicity of Wilms tumor gene product 1 (WT1)-peptide vaccination in WT1-expressing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients without curative treatment option. Vaccination consisted of granulocyte-macrophage colony-stimulating factor subcutaneously days 1 to 4, and WT1.126-134 peptide and 1 mg keyhole limpet hemocyanin on day 3. The initial 9 patients received 4 vaccinations biweekly, then monthly, and the subsequent 10 patients received continual biweekly vaccination. Seventeen AML patients and 2 refractory anemia with excess blasts patients received a median of 11 vaccinations. Treatment was well tolerated. Objective responses in AML patients were 10 stable diseases (SDs) including 4 SDs with more than 50% blast reduction and 2 with hematologic improvement. An additional 4 patients had clinical benefit after initial progression, including 1 complete remission and 3 SDs. WT1 mRNA levels decreased at least 3-fold from baseline in 35% of patients. In 8 of 18 patients, WT1-tetramer(+) T cells increased in blood and in 8 of 17 patients in bone marrow, with a median frequency in bone marrow of 0.18% at baseline and 0.41% in week 18. This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations.


Assuntos
Anemia Refratária com Excesso de Blastos/terapia , Vacinas Anticâncer/uso terapêutico , Imunoterapia Ativa , Leucemia Mieloide/terapia , Fragmentos de Peptídeos/imunologia , Proteínas WT1/imunologia , Doença Aguda , Adjuvantes Imunológicos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/imunologia , Anemia Refratária com Excesso de Blastos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Eritema/etiologia , Feminino , Genes do Tumor de Wilms , Humanos , Esquemas de Imunização , Imunoterapia Ativa/efeitos adversos , Injeções Intradérmicas , Injeções Subcutâneas , Leucemia Mieloide/genética , Leucemia Mieloide/imunologia , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Terapia de Salvação , Especificidade do Receptor de Antígeno de Linfócitos T , Proteínas WT1/administração & dosagem , Proteínas WT1/efeitos adversos
7.
Jpn J Clin Oncol ; 36(4): 231-6, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16611662

RESUMO

OBJECTIVE: We conducted a phase I study to investigate the safety of a weekly WT1 tumor vaccine therapy in patients with solid tumors that had been refractory to all other anti-cancer therapies. METHODS: Skin-test-negative patients were intradermally injected weekly for 12 weeks with 3.0 mg of an HLA-A*2402-restricted modified 9-mer WT1 peptide emulsified in Montanide ISA51 adjuvant. We estimated the Bayesian posterior probability of the occurrence of grade 3 or 4 toxicity when receiving the weekly WT1 vaccination. This analysis provided the basis for making a decision to terminate the phase I study and switch to phase II. Moreover, we performed an exploratory assessment of the anti-tumor effects of WT1 treatment. RESULTS: Ten patients received 114 vaccinations with WT1 on a weekly schedule. No grade 3 or 4 toxicities were observed. Based on the Bayesian approach, it was highly likely that the probability of grade 3 or 4 toxicity was below 20% (the posterior probability = 0.914). Fifteen grade 2 and two grade 1 toxicities were observed; all of these incidents, however, were determined by the Independent Data and Safety Monitoring Committee to be unrelated to the WT1 treatment. One patient exhibited a partial response; five additional patients had stable disease while receiving weekly WT1 treatment. CONCLUSION: This paper confirms that the potential toxicities of the treatment schedule of weekly WT1 vaccination are acceptable and suggested a potential anti-tumor effect. Consequently, we validated the decision to continue to the phase II trial.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Glioblastoma/terapia , Imunoterapia , Proteínas WT1/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Vacinas Anticâncer/efeitos adversos , Feminino , Humanos , Injeções Intradérmicas , Masculino , Pessoa de Meia-Idade , Vacinação , Proteínas WT1/efeitos adversos
8.
Nihon Rinsho ; 63(6): 1101-9, 2005 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-15948398

RESUMO

The Wilms' tumor gene WT1 is overexpressed in leukemia and various types of solid cancers and its product is a tumor rejection antigen. A phase I clinical trials of WT1 peptide-based cancer immunotherapy were performed with good clinical response but with only skin reaction at the injection sites of WT1 vaccine. Thus, WT1-targeting immunotherapy should be promissing.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Proteínas WT1/uso terapêutico , Adenocarcinoma/terapia , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/terapia , Animais , Neoplasias da Mama/terapia , Vacinas Anticâncer/efeitos adversos , Carcinoma de Células Escamosas/terapia , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Leucemia Mieloide Aguda/terapia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Linfócitos T Citotóxicos/imunologia , Proteínas WT1/efeitos adversos
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