RESUMO
BACKGROUND: CIGB-247, a VSSP-adjuvanted VEGF-based vaccine, was evaluated in a phase I clinical trial in patients with advanced solid tumors (CENTAURO). Vaccination with the maximum dose of antigen showed an excellent safety profile, exhibited the highest immunogenicity and was the only one showing a reduction on platelet VEGF bioavailability. However, this antigen dose level did not achieve a complete seroconversion rate in vaccinated patients. These clinical results led us to the question whether a "reserve" of untapped immune response potential against VEGF could exist in cancer patients. To address this matter, CENTAURO-2 clinical trial was conducted where antigen and VSSP dose scale up were studied, and also incorporated the exploration of aluminum phosphate as adjuvant. These changes were made with the aim to increase immune response against VEGF. RESULTS: The present study reports the characterization of the humoral response elicited by CIGB-247 from the combining of different antigen doses and adjuvants. Cancer patients were immunologically monitored for approximately 1 year. Vaccination with different CIGB-247 formulations exhibited a very positive safety profile. Cancer patients developed IgM, IgG or IgA antibodies specific to VEGF. Elicited polyclonal antibodies had the ability to block the interaction between VEGF and its receptors, VEGFR1 and VEGFR2. The highest humoral response was detected in patients immunized with 800 µg of antigen + 200 µg of VSSP. Off-protocol long-term vaccination did not produce negative changes in humoral response. CONCLUSIONS: Vaccination with a human VEGF variant molecule as antigen in combination with VSSP or aluminum phosphate is immunogenic. The results of this study could contribute to the investigation of this vaccine therapy in an adequately powered efficacy trial. TRIAL REGISTRATION: Trial registration number: RPCEC00000155. Cuban Public Clinical Trial Registry. Date of registration: June 06, 2013. Available from: http://registroclinico.sld.cu/ .
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/imunologia , Imunidade Humoral/imunologia , Imunoterapia Ativa , Neoplasias/imunologia , Neoplasias/terapia , Fator A de Crescimento do Endotélio Vascular/imunologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Chlorocebus aethiops , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/sangue , Coelhos , Receptores de Fatores de Crescimento do Endotélio Vascular/sangue , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The development of cancer immunotherapy has long been a challenge. Here, we report that prophylactic vaccination with a highly attenuated Trypanosoma cruzi strain expressing NY-ESO-1 (CL-14-NY-ESO-1) induces both effector memory and effector CD8(+) T lymphocytes that efficiently prevent tumor development. However, the therapeutic effect of such a vaccine is limited. We also demonstrate that blockade of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) during vaccination enhances the frequency of NY-ESO-1-specific effector CD8(+) T cells producing IFN-γ and promotes lymphocyte migration to the tumor infiltrate. As a result, therapy with CL-14-NY-ESO-1 together with anti-CTLA-4 is highly effective in controlling the development of an established melanoma.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Melanoma Experimental/terapia , Proteínas de Membrana/imunologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/parasitologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/parasitologia , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/imunologiaRESUMO
PURPOSE: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG. PATIENTS AND METHODS: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging. RESULTS: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three. CONCLUSION: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.
Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Glioma/imunologia , Imunoterapia Ativa/métodos , Proteínas Inibidoras de Apoptose/imunologia , Indutores de Interferon/imunologia , Poli I-C/imunologia , Receptor EphA2/imunologia , Receptores de Interleucina-13/imunologia , Adolescente , Antígenos de Neoplasias/administração & dosagem , Neoplasias do Tronco Encefálico/imunologia , Vacinas Anticâncer/administração & dosagem , Carboximetilcelulose Sódica/farmacologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Portadores de Fármacos/farmacologia , ELISPOT , Epitopos , Feminino , Humanos , Imuno-Histoquímica , Lactente , Proteínas Inibidoras de Apoptose/administração & dosagem , Injeções Subcutâneas , Indutores de Interferon/administração & dosagem , Subunidade alfa1 de Receptor de Interleucina-13 , Estimativa de Kaplan-Meier , Lisina/farmacologia , Imageamento por Ressonância Magnética , Masculino , Poli I-C/administração & dosagem , Receptor EphA2/administração & dosagem , Receptores de Interleucina-13/administração & dosagem , Survivina , Adulto JovemRESUMO
Salmonella enterica is a facultative anaerobic bacteria, whose ability to colonize antigen-presenting cells (APCs) such as dendritic cells and macrophages, has allowed its successful use as an alive, attenuated bacterial vector for vaccination. Salmonella enterica elicits efficient cellular, humoral and mucosal immune responses, against heterologous antigens including viruses, parasites, other bacterial species and tumor-associated antigens, since it is capable of delivering these antigens to cells of the immune system. The extracellular expression of heterologous antigens on the surface of Salmonella enterica via its type I, III and V secretion systems, and their delivery into infected cells is essential for its stimulation of immune responses against these antigens. Moreover, Salmonella enterica is a promising therapeutic agent against cancer, as demonstrated by reports of pre-clinical and clinical studies indicating that, after systemic administration, Salmonella enterica preferentially localizes in solid tumors and metastases as compared to normal tissues. In this review, we focus on novel prophylactic and therapeutic anti-cancer approaches using Salmonella enterica as a delivery system of heterologous molecules with the aim of inhibiting tumor growth.
Assuntos
Antígenos Heterófilos/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Citocinas/uso terapêutico , Terapia Genética , Vetores Genéticos/uso terapêutico , Imunoterapia Ativa , Neoplasias/terapia , RNA Interferente Pequeno/uso terapêutico , Vacinas contra Salmonella/uso terapêutico , Salmonella enterica/imunologia , Animais , Apresentação de Antígeno , Antígenos Heterófilos/administração & dosagem , Antígenos Heterófilos/genética , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/genética , Sistemas de Secreção Bacterianos , Vacinas Anticâncer/administração & dosagem , Ensaios Clínicos como Assunto , Citocinas/administração & dosagem , Citocinas/genética , Vetores Genéticos/imunologia , Humanos , Camundongos , Neoplasias/imunologia , Neoplasias/microbiologia , Neoplasias/prevenção & controle , Neoplasias Experimentais/microbiologia , Neoplasias Experimentais/terapia , RNA Interferente Pequeno/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Salmonella enterica/fisiologia , Terapêutica , Vacinas Vivas não Atenuadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A proteína Kint3-4 (PKint3-4), codificadora da angiostatina, é reconhecida por sua potencialidade antiangiogênica. O presente estudo teve como objetivo avaliar o efeito da proteína Kint3-4 no crescimento do tumor sólido de Ehrlich. Para isso, foram analisados a curva de desenvolvimento tumoral, o índice apoptótico e a dosagem de hemoglobina, a fim de se avaliar a angiogênese, em 20 camundongos Swiss fêmeas, inoculadas com o tumor sólido de Ehrlich em seus coxins plantares. Os resultados demonstraram a participação de PKint3-4 na indução à apoptose de células neoplásicas, na diminuição da concentração de hemoglobina e, principalmente, na diminuição do desenvolvimento tumoral. Sugere-se que a ação antitumoral, determinada pela sequência proteica utilizada, possa estar associada ao papel antiangiogênico da angiostatina, que indiretamente aumentaria o índice apoptótico das células neoplásicas, e/ou a uma ação direta da proteína Kint3-4 sobre essas células, estimulando-as a sofrerem apoptose.(AU)
Assuntos
Animais , Feminino , Camundongos , Camundongos/fisiologia , Antígenos de Neoplasias/administração & dosagem , Proteínas , Angiostatinas , Hemoglobinas/análise , Células Tumorais CultivadasRESUMO
The effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) administration to normal male hamsters upon serum glucose and triglyceride levels, beta-cell mass and function was studied. INGAP-PP (500 mug) or saline was injected twice daily during 10 days. Both groups showed comparable body weight, serum glucose and triglyceride levels. INGAP-PP treated animals had significantly higher HOMA-IR and HOMA-beta and their islets released more insulin in response to glucose; they had lower islet DNA content, significantly increased number of islets/unit area, beta-cell replication rate and mass, cells co-expressing Pdx-1/INGAP and islets in contact with ducts, and decreased beta-cell apoptosis rate. The percentage of cells expressing Pdx-1 alone or together with INGAP or insulin increased significantly in ducts. These animals also showed a significantly higher concentration of Pdx-1 and Ngn-3 mRNA and a lower number of INGAP-positive cells. In conclusion, INGAP-PP promoted a controlled and functionally active increase of beta-cell mass; our data demonstrate for the first time the mechanism responsible for such changes; that Ngn-3 would be involved in INGAP-PP-induced neogenesis; and the existence of a negative feedback loop with endogenous INGAP-producing cells. Accordingly, INGAP-PP could be used to induce these effects in people with or at risk of developing diabetes.
Assuntos
Antígenos de Neoplasias/farmacologia , Biomarcadores Tumorais/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Antígenos de Neoplasias/administração & dosagem , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores Tumorais/administração & dosagem , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Cricetinae , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Lectinas Tipo C/administração & dosagem , Masculino , Mesocricetus , Proteínas do Tecido Nervoso/genética , Proteínas Associadas a Pancreatite , Fragmentos de Peptídeos/administração & dosagem , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Triglicerídeos/análiseRESUMO
El antígeno del carcinoma de células (AgCCE) es una subfracción purificada del antígeno tumoral 4 (TA-4), glucoproteína localizada en el citoplasma del epitelio escamoso normal y del carcinoma cervicouterino. El AgCCE fue aislado mediante técnicas de inmunoensayo en suero de mujeres sanas y en pacientes con una gran variedad de neoplasias: esófago, piel, canal anal, cabeza y cuello, peso con particular énfasis en carcinoma cervicouterino. Objetivo. Comparar la expresión del AgCCE en mujeres sanas versus pacientes con carcinoma cervicouterino atendidas en el Instituto Nacional de Cancerología de México. Pacientes y métodos. Estudio preliminar para comparar la concentración sérica del AgCCE en 46 mujeres sanas y 56 pacientes con cáncer cervicouterino vírgenes a tratamiento. Se evaluó en ambos grupos la expresión del AgCCE de acuerdo a la edad, etapa clínica, estirpe histológica y grado de diferenciación del tumor. El AgCCE se determinó mediante una muestra de 5.0 mL. Resultados. Se consideró como cifra normal de expresión del AgCCE el intervalo de 0.6-1.3 ng/mL. La media fue de 0.66 ng/mL (intervalo 0.2-1.9) en las mujeres sanas versus 83.3 por ciento de las pacientes con carcinoma cervicouterino (p=0.0005). El 4.4 por ciento de las mujeres sanas versus 83.3 por ciento de las pacientes con cáncer cervicouterino, expresaron el AgCCE con un valor sérico mayor de 1.3 ng/mL (p<0.001). Los porcentajes del AgCCE por esta clínica fueron los siguientes: del 60 por ciento en estadio IB, del 94.2 por ciento en etapa II, del 87.5 por ciento en estadio III y del 100 por ciento en etapa clínica IV. El 100 por ciento para los carcinomas adenoescamosos y el 90.5 por ciento de los de tipo epidermoide expresaron el AgCCE por arriba de 1.3 ng/mL. Los tumores bien y moderadamente diferenciados se expresaron cada uno en el 100 por ciento. Conclusiones. Nuestros resultados revelan que existe correlación entre los carcinomas epidermoides de cérvix y la expresión del AgCCE, pudiendo ser empleado en la detección oportuna de las recurrencias y monitoreo de las pacientes con carcinoma cervicouterino. Con particular énfasis de acuerdo a las dimensiones del tumor primario, etapa clínica, estirpe histológica y grado de diferenciación
Assuntos
Humanos , Feminino , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/classificação , Antígenos de Neoplasias/imunologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Ensaios Clínicos como Assunto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais , Interpretação Estatística de Dados , Neoplasias do Colo do Útero/classificação , Colposcopia , Esfregaço VaginalRESUMO
La metodología clínica en oncología tiene hoy en día una gran utilidad especialmente porque es un instrumento que permite valorar la efectividad de los diversos tratamientos que actualmente se dispone, su importancia es mayor pues ayuda a definir conductas terapeuticas en una especialidad medica que cada día esta sometida a nuevos cambios, El conocimiento de esta rama de oncología es un deber para todo oncologo moderno y la obligación de revisar casuisticas, efectividad de tratamientos, morbimortalidad de los mismos, tasas de sobrevida, le permiten al medico tener una visión global sobre la enfermedad y singular sobre cada paciente, pudiendo adoptar una conducta medica y etica correcta.
Assuntos
Humanos , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/uso terapêutico , Institutos de CâncerAssuntos
Antígenos de Neoplasias/administração & dosagem , Doença Enxerto-Hospedeiro/etiologia , Reação Enxerto-Hospedeiro , Neoplasias Experimentais/imunologia , Animais , Feminino , Rejeição de Enxerto , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , GravidezRESUMO
Preliminary results of active immunotherapy ,both in vitro and in vivo, about ascitical Ehrlich carcinoma transplanted in albinic swiss mice are presented. In the in vitro experiment, tumor cells were marked with the immunoglobulin, anti-tumor-associated antigens (TAA) and were coupled to a dinitrophenyl radical (Ig DNP anti-TAA). These cells were meaningfully hindered from migration in presence of swiss albinic mice's splenic cells. These mice were sensibilized to the tumor cells marked with Ig-DNP. The injection of a Ig-DNP anti-TAA 0,3 ml, every third days, intraperitoneal way, in a span of 21 days, in albinical swiss mice with a transplant of 3 X 10(5) Ehrlich carcinoma cells (group A) 24 hours before, constituted the in vivo test. The growth ought to be compared to an Ig-DNP tolerant group (group B), which received equal quantities of tumor cells and followed the same plan of treatment, as well as to another control group transplanted under the same conditions, but with no treatment (group C). Eight days from the experiment, there was a clear difference between group A and groups B and C. The last two groups died from 13th to the 26th day after the transplant. On the contrary, the whore group A continued alive and with no sign of ascitical tumor. Nevertheless, an animal of group A died after the 28th day, due to a solid tumor in the abdominal wall.