RESUMEN
Increased levels of NeuGc-containing gangliosides have been described in human breast cancer. A controlled Phase II clinical trial was conducted in patients with metastatic breast cancer to evaluate immunogenicity, safety and to identify evidences of biological activity of a cancer vaccine composed by NeuGcGM3 in a proteoliposome of Neisseria meningitidis together with Montanide ISA 51 as adjuvant. After first line chemotherapy, 79 women were randomized 1:1 to receive the vaccine candidate or best supportive care. All patients achieved at least stable disease to the first line therapy for the metastatic condition. Treatment consisted on 5 vaccine doses every 2 weeks and then, monthly re-immunization to complete 15 doses. Vaccination with the NeuGcGM3 based vaccine was safe and the most frequent adverse events consisted on injection site reactions, fever, arthralgia and chills. The vaccine was immunogenic and a sustained increase of both IgG and IgM antibody titters against NGcGM3 was observed after the second vaccination month. Antibodies were able to recognize the NeuGcGM3(+) murine tumor cell line L1210 and the myeloma cell line P3X63. Humoral response was specific since vaccination did not result in Neu-Acetyl GM3 or GM2-antibody response. Hyperimmune sera from vaccinated patients were able to prevent the NeuGcGM3 mediated CD4 down-modulation on T lymphocytes. In the intent to treat analysis, there was a trend toward a survival advantage for the vaccine group and this effect was significant for women bearing non-visceral metastasis. Two phase III clinical studies with this vaccine candidate are ongoing.
RESUMEN
The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize theEGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosedhigh-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy.Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA)(12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated.No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypicresponse. Objective response-rate was 37.9percent (17.2 percent complete response, 20.7 percent partialresponse) while stable disease occurred in 41.4 percent of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients(AU)
El mal pronóstico de los pacientes con glioma de alto grado ha llevado a la búsqueda de nuevos estrategias terapéuticas. Más de la mitad de estos tumores de crecimiento epidérmico overexpress factor receptor (EGFR). h-R3 es un anticuerpo monoclonal humanizado que reconocen la EGFR dominio externo con alta afinidad, inhibiendo la activación de la tirosina cinasa. Con el fin de evaluar la seguridad, inmunogenicidad y eficacia preliminar de h-R3 en el recién diagnosticado glioma de alto grado los pacientes, se realizó una fase I / II de prueba. Los pacientes recibieron seis semanales infusiones de h-R3 en la dosis de 200 mg en combinación con radioterapia de haz externo. Veintinueve pacientes (edad media, 45 años y medio SPK 80) se introdujeron en el estudio. Tipos de tumores fueron: glioblastoma (GB) (16 pacientes), astrocitoma anaplásico (AA) (12 pacientes) y oligodendroglioma anaplásico (AO) (1 paciente). Todos los pacientes fueron sometidos a debulking la cirugía o la biopsia antes de entrar en el juicio. El anticuerpo fue muy bien tolerada. No evidencias de grado 3 / 4 se detectaron efectos adversos. Ninguno de los pacientes desarrollaron Acneiform erupción cutánea o reacciones alérgicas. Un paciente desarrolló una positiva anti-idiotypic respuesta. Objetivo de tipo de respuesta fue de 37,9 por ciento (17,2 por ciento respuesta completa, el 20,7 por ciento parcial respuesta), mientras que la enfermedad estable en el 41,4 por ciento de los pacientes. Con una mediana de seguimiento el tiempo de 29 meses, la mediana de supervivencia de 22,17 meses para todas las materias. La mediana de supervivencia tiempo (MST) es de 17,47 meses GB, mientras que el MST no se llega a los pacientes para AA
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Astrocitoma/terapia , Glioblastoma/terapia , Glioma/patología , Glioma/terapia , Oligodendroglioma/terapiaRESUMEN
The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize the EGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosed high-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy. Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA) (12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated. No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypic response. Objective response-rate was 37.9% (17.2% complete response, 20.7% partial response) while stable disease occurred in 41.4% of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients.