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1.
Curr Top Microbiol Immunol ; 405: 79-97, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-25702159

RESUMO

Several approaches to antigen-specific immunotherapy of cancer antigen-specific immunotherapy of cancer have been tested clinically. In this chapter, we will describe studies done with the antigen MUC1. Tested MUC1 therapeutic vaccines include the following: monoclonal antibodies (MAbs) specific for MUC1; synthetic and recombinant polypeptides from the protein sequence of MUC1; dendritic cells carrying MUC1; RNA and DNA vaccinations; and recombinant viruses carrying the MUC1 DNA sequence. Chemotherapy of cancer aims to be toxic to the cancer cells with manageable side effects to the patient. In contrast, antigen-specific immunotherapy of cancer aims to treat the patient, such that the patient is then able to control and eventually eliminate their cancer cells. It is therefore important to know the immune status of each cancer patient prior to therapy.


Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Mucina-1/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos
2.
PLoS One ; 9(2): e83670, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586226

RESUMO

RATIONAL: While a variety of registered therapies exist for Cutaneous T Cell Lymphoma, no such therapy is available for Cutaneous B Cell Therapy. In this context we performed a phase II, open label, multicenter, non-comparative study to evaluate the efficacy and safety of repeated intra-lesional administrations of TG1042 (adenovirus-interferon-γ) in patients with relapsing primary cutaneous B-cell lymphomas (CBCL). METHOD: Thirteen patients have been enrolled and received intralesional injections of TG1042 containing 5×10(10) viral particles into up to six lesions simultaneously. Injections were performed on days 1, 8 and 15 of each of four consecutive 28 day cycles. RESULTS: Eleven (85%) out of 13 enrolled patients showed an objective response after injections of TG1042. Seven patients (54%) exhibited complete and four (31%) displayed partial response. The median time to disease progression in the study population was 23.5 months (range 6.25 to 26+). Most commonly observed adverse events were minor to moderate flu-like symptoms, fatigue and injection site reactions. CONCLUSIONS: Our study showed that treatment with TG1042 was associated with a clinical benefit in the majority of the patients with relapsing CBCL, including tumor regression, a clinically meaningful duration of response and a good treatment tolerance. TRIAL REGISTRATION: www.clinicaltrials.govNCT00394693.


Assuntos
Adenoviridae/metabolismo , Interferon gama/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Injeções Intralesionais/métodos , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia
3.
Lancet Oncol ; 12(12): 1125-33, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22019520

RESUMO

BACKGROUND: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/tratamento farmacológico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Interleucina-2/genética , Interleucina-2/imunologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/efeitos adversos , Pessoa de Meia-Idade , Mucina-1/genética , Mucina-1/imunologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vacinas Sintéticas , Vaccinia virus/genética , Gencitabina
4.
Cancer Immunol Immunother ; 60(2): 261-71, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21069322

RESUMO

MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10(8) pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4+ T cell proliferative response during therapy. Anti-MUC1 CD8+ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8+ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.


Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Citocinas/imunologia , Citocinas/uso terapêutico , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/uso terapêutico , Adolescente , Adulto , Idoso , Vacinas Anticâncer/administração & dosagem , Carcinoma de Células Renais/imunologia , Proliferação de Células , Citocinas/administração & dosagem , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Neoplasias Renais/imunologia , Masculino , Glicoproteínas de Membrana/administração & dosagem , Pessoa de Meia-Idade , Mucina-1/biossíntese , Mucina-1/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Resultado do Tratamento , Adulto Jovem
5.
Mol Ther ; 18(6): 1244-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20372104

RESUMO

Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-gamma] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy.


Assuntos
Adenoviridae/genética , Interferon gama/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Neoplasias Cutâneas/terapia , Humanos , Injeções Intralesionais , Interferon gama/administração & dosagem , Interferon gama/genética
6.
Expert Rev Vaccines ; 7(7): 889-93, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18767940

RESUMO

Tumor-associated antigens (TAAs) have been formulated into vaccines that, combined with adjuvants, cytokines or other strategies to boost the immune response, are now in clinical development. Both humoral and cellular immune responses to TAAs have been generated using these vaccines. This approach relies on the patient's own immune system generating an effective anti-tumor immune response. The advantage of this over therapy with monoclonal antibodies for the treatment of cancer is that multiple antigenic epitopes can be involved and the immune system is able to adapt to the most effective antigenic specificity for tumor growth control and rejection. In this article, we describe the clinical use of vaccinia virus, in particular modified vaccinia virus Ankara (MVA), to express TAAs in vivo and to stimulate an effective immune response to the cancer antigens.


Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Vetores Genéticos , Neoplasias/prevenção & controle , Neoplasias/terapia , Vaccinia virus/genética , Vacinas Anticâncer/genética , Humanos , Neoplasias/imunologia
7.
J Thorac Oncol ; 3(7): 735-44, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18594319

RESUMO

BACKGROUND: TG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1. METHODS: A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25 mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan-Meier method. RESULTS: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. CONCLUSIONS: The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia , Neoplasias Pulmonares/terapia , Glicoproteínas de Membrana/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Terapia Combinada , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/efeitos adversos , Pessoa de Meia-Idade , Mucina-1/análise , Mucina-1/imunologia , Taxa de Sobrevida , Linfócitos T/imunologia , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina
8.
Mol Ther ; 16(5): 985-94, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18388930

RESUMO

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.


Assuntos
Adenoviridae/genética , Dacarbazina/farmacologia , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Interleucina-2/genética , Melanoma/genética , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
9.
Viral Immunol ; 20(4): 664-71, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18158739

RESUMO

Recombinant vaccinia virus with tumor cell specificity may provide a versatile tool either for direct lysis of cancer cells or for the targeted transfer of genes encoding immunomodulatory or toxic molecules. We report the expression of a tumor-specific single-chain antibody on the surface of intracellular mature vaccinia virus particles (IMV). The wild-type p14 externally membrane-associated protein p14 (A27L gene), which is not required for viral binding and replication, was replaced by p14 fusion molecules carrying a single-chain antibody directed against the tumor-associated antigen MUC-1. MUC-1 mucin is an epithelial cell antigen whose aberrant expression plays a role in autoimmunity and tumor immunity in the majority of human carcinomas and multiple myeloma. Fusion protein carrying the single-chain antibody at the NH2-terminal position was expressed and exposed at the envelope of the corresponding recombinant virus. The construct containing the antibody was able to bind a MUC-1 specific 60mer peptide. Moreover, targeted virus infects MUC-1-expressing cells in vitro more efficiently.


Assuntos
Anticorpos Antivirais/imunologia , Neoplasias/terapia , Vaccinia virus/genética , Vaccinia virus/imunologia , Animais , Anticorpos Antivirais/uso terapêutico , Antígenos de Neoplasias/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral , Vetores Genéticos , Humanos , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Proteínas de Membrana , Camundongos , Mucinas/imunologia , Neoplasias/genética , Neoplasias/imunologia , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Vacínia/virologia , Vaccinia virus/crescimento & desenvolvimento , Vaccinia virus/isolamento & purificação , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/imunologia
10.
J BUON ; 12 Suppl 1: S71-5, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17935281

RESUMO

Vaccines are well known in the context of prevention of diseases caused by infectious agents. Current research is now aimed at using vaccines to manipulate the immune system to eliminate established diseases, including cancer. Several such immunotherapeutic vaccines are now in clinical trials and are beginning to show clinical benefit. TG4010 is one such vaccine. It incorporates the MUC1 antigen, which is overexpressed in the majority of cancers, into a non-propagative pox viral vector, MVA. A second gene, interleukin-2 is also incorporated into TG4010 as an immune stimulus. The vaccine has been tested in breast, kidney, prostate and lung cancers with encouraging results.


Assuntos
Vacinas Anticâncer/uso terapêutico , Vetores Genéticos , Imunoterapia/métodos , Interleucina-2/imunologia , Glicoproteínas de Membrana/uso terapêutico , Mucina-1/imunologia , Neoplasias/terapia , Poxviridae/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Feminino , Humanos , Interleucina-2/genética , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Glicoproteínas de Membrana/imunologia , Mucina-1/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Resultado do Tratamento
11.
J Clin Invest ; 117(10): 2834-46, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17823660

RESUMO

The fact that adenoviral vectors activate innate immunity and induce type I IFNs has not been fully appreciated in the context of cancer gene therapy. Type I IFNs influence different aspects of human immune response and are believed to be crucial for efficient tumor rejection. We performed transcriptional profiling to characterize the response of cutaneous lymphomas to intralesional adenovirus-mediated IFN-gamma (Ad-IFN-gamma) gene transfer. Gene expression profiles of skin lesions obtained from 19 cutaneous lymphoma patients before and after treatment with Ad-IFN-gamma revealed a distinct gene signature consisting of IFN-gamma- and numerous IFN-alpha-inducible genes (type II- and type I-inducible genes, respectively). The type I IFN response appears to have been induced by the vector itself, and its complexity, in terms of immune activation, was potentiated by the IFN-gamma gene insert. Intralesional IFN-gamma expression together with the induction of a combined type I/II IFN response to Ad-IFN-gamma gene transfer seem to underlie the objective (measurable) clinical response of the treated lesions. Biological effects of type I IFNs seem to enhance those set in motion by the transgene, in our case IFN-gamma. This combination may prove to be of therapeutic importance in cytokine gene transfer using Ads.


Assuntos
Adenoviridae/imunologia , Vetores Genéticos/imunologia , Imunidade Inata/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Linfoma/imunologia , Neoplasias Cutâneas/imunologia , Adenoviridae/genética , Células Cultivadas , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos/genética , Humanos , Linfoma/genética , Linfoma/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia
12.
IDrugs ; 10(5): 324-8, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17487784

RESUMO

Therapeutic vaccination against cancer-associated antigens represents an attractive option for cancer therapy in view of its efficacy, the possibility of long-lasting immunity against the cancer, and safety profile. Nevertheless, it is now recognized that the same vaccination strategies used for prophylactic vaccinations against infectious diseases, cannot necessarily be used for therapeutic cancer vaccination. Cancer patients are usually immunosuppressed and most cancer-associated antigens are 'self-antigens', making it a significant challenge to vaccinate patients against a cancer-associated antigen. Various immunostimulation techniques are under investigation in an effort to bolster patients' immune systems and to overcome immune tolerance to self antigens. Strategies to stimulate antigen presentation, T-cell reactivity and innate immune activity are under investigation. Several clinical trials have been conducted to evaluate therapeutic cancer vaccines in patients, and attractive protocols, including those that combine the stimulation of specific T-cells and chemotherapy, or strategies to block immune regulation, are beginning to show some success. This feature review considers strategies for the development of effective therapeutic cancer vaccines, and highlights select vaccines that have already entered the clinic.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Anticâncer/uso terapêutico , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Neoplasias/efeitos dos fármacos , Vias de Administração de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/imunologia , Neoplasias/prevenção & controle , Vacinação/métodos , Vacinação/tendências
13.
Curr Opin Drug Discov Devel ; 10(2): 185-92, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17436554

RESUMO

Over the past century, various efforts have been made to induce the rejection of cancerous tissues by the stimulation of an immune reaction, using both non-specific and antigen-specific strategies. Non-specific approaches attempt to augment an immune response in and around the tumor by injecting immune stimulating substances, for example, bacterial extracts, cytokines or gene therapy agents. Antigen-specific approaches use either the tumor cells themselves as a source of antigens or incorporate identified tumor-associated antigens into vaccines. This review describes antigen-specific therapeutic cancer vaccines that are currently in development.


Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias/prevenção & controle , Neoplasias/terapia , Animais , Humanos , Imunoterapia , Neoplasias/imunologia
14.
Bull Cancer ; 94(3): 253-7, 2007 Mar.
Artigo em Francês | MEDLINE | ID: mdl-17371767

RESUMO

MUC1 is a large, highly glycosylated protein expressed on the apical membrane of many epithelial cells. With other members of the mucin family it contributes to the protection and function of mucosal cells. The intracellular part of the protein may also participate in signal transduction pathway, through multiple interactions with intracellular proteins. Overexpression of MUC1 is frequently observed in the majority of epithelial cancers and even in some haematological malignancies. In tumor cells, MUC1 loses apical distribution and is hypoglycosylated. These cancer-associated changes render it antigenic and make it an attractive target for a specific cancer immunotherapy. Several MUC1-based therapeutic cancer vaccines are currently under clinical investigation.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Mucinas/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/terapia , Antígenos de Neoplasias/fisiologia , Vacinas Anticâncer/imunologia , Humanos , Glicoproteínas de Membrana/uso terapêutico , Mucina-1 , Mucinas/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias/imunologia , Neoplasias/metabolismo
15.
Cancer Res ; 65(20): 9536-46, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16230419

RESUMO

To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity.


Assuntos
Imunoterapia Ativa/métodos , Interleucina-18/imunologia , Interleucina-2/imunologia , Proteínas Recombinantes de Fusão/imunologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Glicoproteínas/metabolismo , Humanos , Imunidade Inata/imunologia , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-18/biossíntese , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-2/biossíntese , Interleucina-2/genética , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2 , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Linfócitos T/imunologia
16.
Expert Rev Vaccines ; 4(4): 493-502, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16117706

RESUMO

The cancer-associated antigen MUC1 is overexpressed and modified by tumor cells in over half of all cancer cases. Despite various complexities associated with this antigen, it is well worth pursuing as a vaccine for the immunotherapy of cancer. In this review, the authors describe the discovery of MUC1 and its association with cancer, recent observations showing that the immunology of MUC1 is complicated, animal data showing that it can be a target for immune-mediated tumor rejection, and finally, preliminary clinical results to show that vaccine-based immunotherapy with MUC1 does have an impact on the therapy of cancer.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Mucina-1/imunologia , Neoplasias/imunologia , Neoplasias/prevenção & controle , Animais , Vacinas Anticâncer/imunologia , Humanos , Imunoterapia/tendências
17.
Discov Med ; 5(25): 25-9, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20704919

RESUMO

Extract: Cancer cells are able to escape immune detection and/or rejection by a variety of measures. Cell surface molecules, which are required for the effective policing of tissues by the immune system, are often modified, reduced or eliminated. In addition cancer cells secrete soluble molecules that inhibit the patients' ability to develop an immune response. The ability of the immune system to recognize and reject cancerous growths has been demonstrated in a series of experimental model systems. Efforts are now being made to use this knowledge for the treatment of cancer. Described below are two different gene-based approaches to stimulate the rejection of an established cancer in patients. The first involves procedures which modify the tumor itself, render it a more attractive target to the immune system, and allow immune cells to penetrate the tumor and kill the cancerous cells. The second approach requires a very powerful vaccine to stimulate a strong immune response against the tumor associated antigens in patients with an established cancer. Early efforts to harness the power of the immune system to eliminate cancer were made by Dr. William Coley very early in the 20th century. Dr. Coley injected cancerous tissue, usually sarcomas (tumors of the supportive tissues such as bone, cartilage fat or muscle), with a mix of bacteria and/or their toxins. This would result in an inflammatory response in the tumor and the influx of many immune cells.

18.
Cancer Gene Ther ; 12(2): 198-205, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15472713

RESUMO

Recent evidence has resurrected the concept of specialized populations of T lymphocytes that are able to suppress an antigen-specific immune response. T-regulatory cells (T-reg) have been characterized as CD4+ CD25+ T cells. Previous reports describing differential gene expression analysis have shown that the glucocorticoid-induced tumor necrosis family receptor family-related gene (GITR) is upregulated in these cells. Furthermore, antibodies specific for GITR have been shown to inhibit the T-suppressor function of CD4+ CD25+ T-reg. The ligands for both mouse and human GITR have been cloned recently. We have inserted the sequences for natural, membrane-bound GITR-ligand (GITR-L) and a truncated secreted form of GITR-L (GITR-Lsol) into the adenovirus-5 genome. Coculture experiments show that cells infected with Ad-GITR-L and supernatants from cells infected with Ad-GITR-Lsol can increase the proliferation of both CD4+ CD25- and CD8+ T cells in response to anti-CD3 stimulation, in the presence, as well as in the absence, of CD4+ CD25+ T cells. The virus constructs were injected into growing B16 melanoma tumors. Ad-GITR-L was shown to attract infiltration with both CD4+ and CD8+ T cells. Both constructs were shown to inhibit tumor growth.


Assuntos
Adenoviridae/genética , Antígenos CD4/análise , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Melanoma Experimental/terapia , Linfócitos T Reguladores/fisiologia , Animais , Antígenos CD28/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/uso terapêutico , Proliferação de Células , Técnicas de Cocultura , Feminino , Terapia de Imunossupressão , Ligantes , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos , Fatores de Necrose Tumoral
19.
Cancer Immunol Immunother ; 54(6): 548-56, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15599528

RESUMO

Efforts to follow tumor-specific immune responses in patients are often thwarted by lack of knowledge of the appropriate tumor antigens and the CTL epitopes of those antigens. There is, therefore, a growing need for techniques to monitor tumor-specific immune responses in settings where tumor antigens, and antigenic epitopes, remain unidentified. Here we describe a novel system to follow tumor-specific CTL immune responses. A truncated, soluble murine class I MHC (H-2Db) molecule was fused with a rat IgG2a Fc, in order to allow secretion of the complex. Tumor-specific CTL could then be detected as a result of the complex fastening to specific T cell receptors (TCR). These constructs were inserted into the genome of a recombinant adenovirus vector. Infection of tumor cells with these adenovirus constructs results in the secretion of the complexes into the culture supernatant. These soluble divalent class I MHC molecules were used to detect and activate specific CTL populations.


Assuntos
Antígenos H-2/metabolismo , Imunoglobulina G/metabolismo , Neoplasias/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Linfócitos T Citotóxicos/imunologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Citometria de Fluxo , Antígenos H-2/genética , Antígeno de Histocompatibilidade H-2D , Humanos , Imunoglobulina G/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Ratos
20.
Proc Natl Acad Sci U S A ; 101 Suppl 2: 14567-71, 2004 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-15333750

RESUMO

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFN gamma construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Vacinas de DNA/uso terapêutico , Antígenos de Neoplasias , Neoplasias da Mama/terapia , Vacinas Anticâncer/genética , Citocinas/genética , Feminino , Terapia Genética , Humanos , Neoplasias Renais/terapia , Neoplasias Pulmonares/terapia , Masculino , Neoplasias/imunologia , Infecções por Papillomavirus/terapia , Neoplasias da Próstata/terapia , Neoplasias do Colo do Útero/terapia , Vacinas de DNA/genética
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