Safety and Immunogenicity of a Human Papillomavirus Peptide Vaccine (CIGB-228) in Women with High-Grade Cervical Intraepithelial Neoplasia: First-in-Human, Proof-of-Concept Trial

Objective. CIGB-228 is a novel therapeutic vaccine consisting of HLA-restricted HPV16 E7 epitope adjuvated with VSSP. This trial was designed to evaluate the toxicity, safety, immunogenicity, HPV clearance, and lesion regression. Methods. Seven women were entered. All were HLA-A2 positive, had biopsy-proven high-grade CIN, histologically positive for HPV16, and beared persistent postbiopsy lesions visible by digital colposcopy. HLA-A2 women with biopsy-proven high-grade CIN, HPV16-positive, and beared persistent postbiopsy lesions visible by digital colposcopy were vaccinated. One weekly injections of CIGB-228 vaccine was given for four weeks. Then, loop electrosurgical excision procedure (LEEP) of the transformation zone was performed. Study subjects were followed for 1 year after LEEP. Results. No toxicity beyond grade 1 was observed during and after the four vaccinations. Five of seven women had complete and partial regression. Cellular immune response was seen in all patients. HPV was cleared in three of the patients with complete response. Conclusion. CIGB-228 vaccination was well tolerated and capable to induce IFNγ-associated T-cell response in women with high-grade CIN. In several patients, lesion regression and HPV clearance were observed

CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research

CK2 represents an oncology target scientifically validated. However, clinical research with inhibitors of the CK2-mediated phosphorylation event is still insufficient to recognize it as a clinically validated target. CIGB-300, an investigational peptide-based drug that targets the phosphoaceptor site, binds to a CK2 substrate array in vitro but mainly to B23/nucleophosmin in vivo. The CIGB-300 proapoptotic effect is preceded by its nucleolar localization, inhibition of the CK2-mediated phosphorylation on B23/nucleophosmin and nucleolar disassembly. Importantly, CIGB-300 shifted a protein array linked to apoptosis, ribosome biogenesis, cell proliferation, glycolisis, and cell motility in proteomic studies which helped to understand its mechanism of action. In the clinical ground, CIGB-300 has proved to be safe and well tolerated in a First-in-Human trial in women with cervical malignancies who also experienced signs of clinical benefit. In a second Phase 1 clinical trial in women with cervical cancer stage IB2/II, the MTD and DLT have been also identified in the clinical setting. Interestingly, in cervical tumors the B23/nucleophosmin protein levels were significantly reduced after CIGB-300 treatment at the nucleus compartment. In addition, expanded use of CIGB-300 in case studies has evidenced antitumor activity when administered as compassional option. Collectively, our data outline important clues on translational and clinical research from this novel peptide-based drug reinforcing its perspectives to treat cancer and paving the way to validate CK2 as a promising target in oncology.Fil: Perea, Silvio E.. Center for Genetic Engineering and Biotechnology; CubaFil: Baladron, Idania. Center for Genetic Engineering and Biotechnology; CubaFil: Garcia, Yanelda. Center for Genetic Engineering and Biotechnology; CubaFil: Perera, Yasser. Center for Genetic Engineering and Biotechnology; CubaFil: Lopez, Adlin. Center for Genetic Engineering and Biotechnology; CubaFil: Soriano, Jorge L.. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Batista, Noyde. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Palau, Aley. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Hernández, Ignacio. Center for Genetic Engineering and Biotechnology; CubaFil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Idrian. Center for Genetic Engineering and Biotechnology; CubaFil: Gonzalez, Lidia. Center for Genetic Engineering and Biotechnology; CubaFil: Gil, Jeovanis. Center for Genetic Engineering and Biotechnology; CubaFil: Rodriguez, Arielis. Center for Genetic Engineering and Biotechnology; CubaFil: Solares, Margarita. Center for Genetic Engineering and Biotechnology; CubaFil: Santana, Agueda. Center for Genetic Engineering and Biotechnology; CubaFil: Cruz, Marisol. Center for Genetic Engineering and Biotechnology; CubaFil: Lopez, Matilde. Center for Genetic Engineering and Biotechnology; CubaFil: Valenzuela, Carmen. Center for Genetic Engineering and Biotechnology; CubaFil: Reyes, Osvaldo. Center for Genetic Engineering and Biotechnology; CubaFil: López Saura, Pedro A.. Center for Genetic Engineering and Biotechnology; CubaFil: González, Carlos A.. Center for Genetic Engineering and Biotechnology; CubaFil: Diaz, Alina. Center for Genetic Engineering and Biotechnology; CubaFil: Castellanos, Lila. Center for Genetic Engineering and Biotechnology; CubaFil: Sanchez, Aniel. Center for Genetic Engineering and Biotechnology; CubaFil: Betancourt, Lazaro. Center for Genetic Engineering and Biotechnology; CubaFil: Besada, Vladimir. Center for Genetic Engineering and Biotechnology; CubaFil: González, Luis J.. Center for Genetic Engineering and Biotechnology; CubaFil: Garay, Hilda. Center for Genetic Engineering and Biotechnology; CubaFil: Gómez, Roberto. Center for Genetic Engineering and Biotechnology; CubaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Perrin, Phillipe. No especifíca;Fil: Renualt, Jean Yves. No especifíca;Fil: Sigman, Hugo. No especifíca;Fil: Herrera, Luis. Center for Genetic Engineering and Biotechnology; CubaFil: Acevedo, Boris. Center for Genetic Engineering and Biotechnology; Cub

Therapeutic angiogenesis following intramuscular gene transfer of vascular endothelial growth factor 121 in a dog model of hindlimb ischemia

Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, has been shown to promote therapeutic angiogenesis in animal models of critical limb ischemia. Ischemic skeletal muscle is advantageous for taking up and expressing foreign genes transferred as naked plasmid DNA. Accordingly, we investigated the hypothesis that intramuscular administration of naked plasmid DNA encoding the 121-amino acid isoform of VEGF could augment collateral development and tissue perfusion in a dog hindlimb ischemia model. Unilateral hindlimb ischemia was surgically induced in Beagle dogs. Ten days later, animals received intramuscular injections of pVEGF121 plasmid directly in the ischemic muscles. Angiogenic effects were evaluated by angiography, calf blood pressure ratio and vasomotor reserve analyses. Thirty days after gene transfer, angiographically recognizable collateral vessels were increased in pVEGF121-treated animals compared with controls. Improvement in perfusion to the ischemic limb was documented by a significantly higher calf blood pressure ratio for pVEGF121 (0.79 \ub1 0.05) versus controls (0.56 \ub1 0.14, P<0.01). Vasomotor reserve assay suggested amelioration in blood availability at the microcirculation level in pVEGF121-treated animals. Hematological variables showed no significant modification due to the treatment. Our results suggest that intramuscular gene transfer of VEGF121 may promote therapeutic angiogenesis in critical limb vascular insufficiency

Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study

<p>Abstract</p> <p>Background</p> <p>Aggressive non-melanoma skin cancer (deeply infiltrating, recurrent, and morphea form lesions) are therapeutically challenging because they require considerable tissue loss and may demand radical disfiguring surgery. Interferons (IFN) may provide a non-surgical approach to the management of these tumors. The aim of this work was to evaluate the effect of a formulation containing IFNs-α and -γ in synergistic proportions on patients with recurrent, advanced basal cell (BCC) or squamous cell skin carcinomas (SCSC).</p> <p>Methods</p> <p>Patients with extensive, recurrent, resistant to other procedures BCC or SCSC received the IFN formulation peri- and intralesionally, three times per week for 3 weeks. They had been previously treated with surgery and/or radiotherapy or chemotherapy. Thirteen weeks after the end of treatment, the original lesion sites were examined for histological evidence of remaining tumor.</p> <p>Results</p> <p>Sixteen elder (median 70 years-old) patients were included. They beared 12 BCC and 4 SCSC ranging from 1.5 to 12.5 cm in the longest dimension. At the end of treatment 47% CR (complete tumor elimination), 40% PR (>30% tumor reduction), and 13% stable disease were obtained. None of the patients relapsed during the treatment period. The median duration of the response was 38 months. Only one patient with complete response had relapsed until today. Principal adverse reactions were influenza-like symptoms well known to occur with interferon therapy, which were well tolerated.</p> <p>Conclusion</p> <p>The peri- and intralesional combination of IFNs-α and -γ was safe and showed effect for the treatment of advanced, recurrent and resistant to previous treatments of BCC and SCSC in elder patients. This is the first report of such treatment in patients with advance non-melanoma skin cancer. The encouraging result justifies further confirmatory trials.</p> <p>Trial registration</p> <p>Current Controlled Trials RPCEC00000052.</p

REPORTE CORTO / SHORT REPORT - THE IFN ganma PATHOPHYSIOLOGY. THE ROLE OF SOLUBLE IFNganmaR alpha CHAIN

Some experimental findings point to a disease-promoting role of IFNganma in several pathological status as multiple sclerosis, systemic lupus erithematosus, type I diabetes, septic shock and others. In the case of rheumatoid arthritis (RA) specially the route of administration are of critical importance in determining the effects of IFNganma. We showed for the first time the altered levels of the IFNganmaR alpha chain in patients with AR and some RFLP of genomic DNA. The IFNganmaR alfa chain soluble fragment was cloned and expressed in E. coli

REPORTE / CORTO - ESTUDIO DE PENETRABILIDAD DEL FACTOR DE CRECIMIENTO EPIDERMICO APLICADO TOPICAMENTE EN VOLUNTARIOS SANOS

La poca penetrabilidad demostrada sugiere que la molecula es preferencialmente captada por los receptores localizados en las celulas del epitelio cutaneo asi como de los fibroblastos presentes en la dermis, por lo que contribuye a la seguridad del producto, reduciendo la posibilidad de efectos adversos sistemicos o a distancia

REPORTE CORTO / SHORT REPORT - EFECTO DEL INTERFERON ALFA (LEUCOCITARIO O RECOMBINANTE) O FACTOR, DE TRANSFERENCIA EN LA SUPERVIVENCIA DE INDIVIDUOS ASINTOMATICOS INFECTADOS POR EL VIRUS DE LA INMUNODEFICIENCIA HUMANA

En 1986 comenzo un estudio de uso de IFN alfa leucocitario o Factor de Transferencia en individuos infectados por VIH y en un estadio clinico correspondiente a los grupos CDC II (asintomatico) o III (linfadenopatia generalizada). En 1987 comenzo un estudio aleatorizado de uso de IFN alfa recombinante o no tratamiento en individuos con las mismas caracteristicas. Estos estudios tenian como objetivo obtener retraso en la progresion de la enfermedad (paso a grupo CDC IV) y terminaron en febrero de 1992, pero los pacientes continuan bajo seguimiento clinico. En este trabajo se reporta que los tratamientos tambien tuvieron un efecto beneficioso sobre la supervivencia de los individuos tratados

ARTICULO ORIGINAL COMPLETO / ORIGINAL FULL PAPER - CLINICAL AND IMMUNOLOGICAL EVALUATION OF ASTHMATIC PATIENTS IN A DOUBLE BLIND TREATMENT PROTOCOL WITH TRANSFER FACTOR

We evaluated clinically and immunologically the therapeutic effect of Transfer Factor (TF) in 17 patients with mild or moderate-severity extrinsic bronchial asthma. TF (1 U) or placebo was administered following a double blind protocol during 6 months (32 doses). The immunological evaluation of the patients and of 21 normal individuals, consisted in immediate hypersensitivity skin tests for common environmental allergens, delayed hypersensitivity tests (DH) for tuberculin (PPD), C. albicans and T. rubrum, total serum IgE (PRIST), specific serum IgE (RAST), eosinophils count, and CD3+, CD4+ and CD8+ lymphocyte subpopulation counts using the avidin-biotin method. The patients presented 3.05 +/- 1.6 crises per month and used frequently beta-adrenergic drugs and teofiline. Before treatment, there was a higher proportion of positive allergic reactivity skin tests (p < 0.01), higher serum IgE levels (p < 0.001) and eosinophils counts (p < 0.01) among patients than in controls. The CD3+ lymphocyte percentage was less in the patients (p < 0.05) as well as the intensity of the DH tests for C. albicans and T. rubrum (p < 0.05). These data confirm the atopic condition of the selected patients. After treatment, there was clinical improvement, decrease in the frequency of crisis as compared to before treatment (p < 0.001), decrease in the frequency and intensity of cough (p < 0.003) and in the use of conventional drugs (p < 0.002). The DH response to PPD and C. albicans was more intense after treatment (p < 0.02). CD3+, CD4+, and CD8+ subpopulations were not modified, so it will be convenient to study T-cell function further. These results indicate that TF improved the clinical condition but did not modify DH reactivity of the patients. The normalization of the cell immunity tests could be associated to clinical improvement, but the correlation between these immunological and clinical parameters requires a larger number of evaluations. RESUMEN Evaluamos clinica e inmunologicamente el efecto terapeutico del Factor de Transferencia (FT) en 17 pacientes con asma bronquial extrinseca de severidad leve o moderada, bajo un protocolo a doble ciegas aplicando 32 dosis (1 U/mL) del FT o de placebo durante 6 meses. La evaluacion inmunologica de los pacientes y de 21 individuos normales, consistio en pruebas de piel para hipersensibilidad inmediata para alergenos ambientales comunes, y retardada (HR) para tuberculina (PPD), C. albicans y T. rubrum, IgE serica total (PRIST), IgE serica especifica (RAST), eosinofilia y cuantificacion de subpoblaciones linfocitarias CD3+, CD4+ y CD8+, con el metodo de la avidina biotina. Los pacientes presentaron 3.05 +/- 1.6 crisis por mes y utilizaban frecuentemente beta-adrenergicos y teofilina. Antes del tratamiento, el estudio de la reactividad alergica en piel demostro un porcentaje de positividad mas elevados en los pacientes que en los controles (p < 0.01), niveles de IgE serica total y eosinofilia tanbien mas elevados en pacientes que en controles (p < 0.001 y p <0.01 respectivamente). El porcentaje de linfocitos CD3+ fue menor en los pacientes (p < 0.05), y asi mismo la intensidad de las pruebas de hipersensibilidad retardada para C. albicans y T. rubrum (p < 0.05). Estos datos confirman la condicion atopica de los pacientes seleccionados. Despues del tratamiento se observo mejoria clinica, se demostro una disminucion en el numero de crisis de asma por mes comparado con el numero de crisis antes del tratamiento (p < 0.001), disminucion de la frecuencia e intensidad de la tos (p < 0.003) y disminucion del uso de medicamentos convencionales (p < 0.002). La respuesta hipersensibilidad retardada al PPD y a C. albicans fue mas intensa despues del tratamiento (p < 0.02). Las subpoblaciones CD3+, CD4+, y CD8+ no se modificaron despues del tratamiento, por lo que seria adecuado estudiar con mas profundidad la funcion de celulas T. Estos resultados indican que el FT mejoro la condicion clinica y no modifico la reactividad de HR de los pacientes. La normalizacion de las pruebas de inmunidad celular podria estar asociada a la mejoria clinica, sin embargo, la asociacion entre estos parametros inmmunologicos y clinicos requiere mayor numero de evaluaciones

Interferon alfa-2B Y Esquizofrenia. Compendio de Las investigaciones clinicas realizadas

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