Tania Crombet Ramos

Phase II Randomized Controlled Trial of an Epidermal Growth Factor Vaccine in Advanced Non–Small-Cell Lung Cancer

PURPOSE We show the result of a randomized phase II clinical trial with an epidermal growth factor (EGF)-based cancer vaccine in advanced non-small-cell lung cancer (NSCLC) patients, evaluating immunogenicity, safety, and effect on survival. PATIENTS AND METHODS Eighty patients with stage IIIB/IV NSCLC after finishing first-line chemotherapy were randomly assigned to receive best supportive care or EGF vaccinations. RESULTS Vaccination was safe. Adverse events were observed in less than 25% of cases and were grade 1 or 2 according to National Cancer Institute Common Toxicity Criteria. Good anti-EGF antibody response (GAR) was obtained in 51.3% of vaccinated patients and in none of the control group. Serum EGF concentration showed a major decrease in 64.3% of vaccinated patients. GAR patients survived significantly more than those with poor antibody response (PAR). Also, patients whose serum EGF dropped below 168 pg/mL survived significantly more than the rest. There was a trend to an increased survival for vaccinated patients compared with controls. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with age younger than 60 years. CONCLUSION Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF. There was a direct correlation between antibody response and survival. There was a direct correlation between decrease in serum EGF and survival. In patients younger than 60 years, vaccination was associated with increased survival.

Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: Report from a phase I/II trial

The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumours over-express 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 6 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.

Treatment of NSCLC patients with an EGF-based cancer vaccine: report of a Phase I trial.

Epidermal Growth Factor (EGF) promotes tumor cell proliferation and survival upon binding to its receptor. We have developed a new active specific immunotherapy based on EGF deprivation. In the present paper, we show the results of a Phase I trial in 43 patients with advanced non-small cell lung cancer (NSCLC) who received the EGF vaccine. Patients who had already received first line therapy were randomized to receive a single or double dose of the EGF vaccine, weekly for four weeks and monthly thereafter. No significant toxicity was seen after vaccination. Adverse events consisted primarily of fever, chills, nausea, vomiting and flushing. Fifteen patients (39%) developed a good antibody response (GAR) against EGF. The geometric mean of the antibody titer was higher in the double dose group. EGF concentration was quantified in serum. An inverse correlation between anti-EGF antibody titers and EGF concentration was seen after immunization. Vaccinated patients achieved median survival times of 8.23 months from randomization. Patients who received the double dose of treatment showed a trend toward increased survival in comparison with patients who received the single dose. GAR and patients in whom the serum EGF decreased below the 168 pg/ml cut-off point had a significantly better survival when compared to poor responders or patients in which the EGF levels were not considerably reduced. Our results confirm the immunogenicity of the EGF vaccine in the treatment of patients with advanced stage NSCLC. Antibody titers and serum EGF levels appear to correlate with patient survival.

Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy.

Background: Over-expression of epidermal growth factor receptor in esophageal cancer is associated with poor prognosis. The present study was conducted to evaluate safety and preliminary efficacy of nimotuzumab, a humanized anti-EGFR antibody in combination with radiation and chemotherapy in advanced esophageal tumours. Patients and Methods: A Phase II clinical trial was conducted, where patients received cisplatin, 5-fluorouracil, and radiotherapy, either alone or combined with six weekly infusions of nimotuzumab at the dose of 200 mg. Safety was the primary endpoint. The antitumoral objective response rate was the secondary endpoint. Epidermal growth factor receptor expression, KRAS mutation status and anti-idiotypic response were also evaluated. Results: Sixty-three patients were included in the study. Thirty patients were entered into the control group, and thirty-three patients received the treatment with nimotuzumab. The antibody was very well tolerated. Objective response rate was 47.8 % (nimotuzumab group) and 15.4 % (control group). Disease control rate was 60.9 % (nimotuzumab group) and 26.9 % (control group). Response and disease control rate were higher in patients with EGFR overexpressing tumors. Conclusion: Nimotuzumab plus chemoradiotherapy was safe and provided statistically significant objective response. A Phase III in patients with similar characteristics will be launched.

Treatment of children with high grade glioma with nimotuzumab: A 5-y institutional experience

Brain tumors are a major cause of cancer-related mortality in children. Overexpression of epidermal growth factor receptor (EGFR) is detected in pediatric brain tumors and receptor density appears to increase with tumor grading. Nimotuzumab is an IgG1 antibody that targets EGFR. Twenty-three children with high-grade glioma (HGG) were enrolled in an expanded access program in which nimotuzumab was administered alone or with radio-chemotherapy. The mean number of doses was 39. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis.

Immunosenescence and gender: a study in healthy Cubans

BackgroundThe progressive decline in the immune function during ageing is termed immunosenescence. Previous studies have reported differences between males and females in the distribution and cell responses of lymphocyte subsets. Most studies of immunosenescence have been done in populations of industrialized countries living in a rather cold environment, and facing lower antigenic challenges such as Cytomegalovirus (CMV). The aim of this study was to determine the effect of ageing on lymphocytes in a population with a high prevalence of CMV infection in all ages, and to compare gender differences related to the immunosenescence markers.ResultsDifferent populations of peripheral blood leukocytes from healthy young and old IgG-CMV seropositive individuals were examined using flow cytometry. With age, the number and frequency of B cells and T cells significantly decreased, while highly differentiated T cells increased. Such changes were different in males and females. The age-associated decline of less differentiated lymphocyte subsets (CD19, CD4 and CD8 cells) and the increase of highly differentiated T cells were more prominent in females. In males, there were no significant changes in CD19, CD4 and CD8 subsets but there was a significant increase in the proportion of highly differentiated T cells.ConclusionShifts in lymphocyte subsets distribution were influenced by age and gender in an IgG-CMV seropositive population. These results suggest different patterns of immunosenescence in respect to gender differences. These patterns could have implications in the design of immunotherapy in the elderly.

CIMAvax EGF (EGF-P64K) vaccine for the treatment of non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) is overexpressed in many epithelial tumors and its role in the development of non-small-cell lung cancer (NSCLC) is widely documented. CIMAvax-EGF is a therapeutic cancer vaccine composed by recombinant EGF conjugated to a carrier protein and emulsified in Montanide ISA51. Vaccination induces antibodies against self-EGF that block EGF–EGFR interaction and inhibit EGFR phosphorylation. Five clinical trials were conducted to optimize vaccine formulation and schedule. Then, two randomized studies were completed in advanced NSCLC, where CIMAvax-EGF was administered after chemotherapy, as ‘switch maintenance’. The vaccine was very well tolerated and the most frequent adverse events consisted of grade 1/2 injection site reactions, fever, headache, vomiting and chills. CIMAvax was immunogenic and EGF concentration was reduced after vaccination. Subjects receiving a minimum of 4 vaccine doses had a significant survival advantage. NSCLC patients with high EGF concentration at baseline had the largest benefit, comparable with best maintenance therapies.

Pilot study of a novel combination of two therapeutic vaccines in advanced non-small-cell lung cancer patients

Abstract Cancer vaccines contain tumor antigens in a pro-inflammatory context with the purpose to generate potent antitumor immune responses. However, tumor cells develop different immunosuppressive mechanisms that limit the effectiveness of an anticancer immune response. Therefore, therapeutic vaccine treatment alone is usually not sufficient to generate tumor regression or survival improvement, especially in the advanced disease scenario in which most clinical studies have been conducted. Combining cancer vaccines with different anticancer therapies such as chemotherapy, radiotherapy and other immunotherapeutic agents has had different levels of success. However, the combination of cancer vaccines with different mechanisms of action has not been explored in clinical trials. To address this issue, the current review summarizes the main clinical and immunological results obtained with two different therapeutic vaccines used in advanced non-small-cell lung cancer patients, inducing an immune response against epidermal growth factor (CIMAvax-EGF) and NGcGM3 ganglioside (racotumomab). We also discuss preliminary findings obtained in a trial of combination of these two vaccines and future challenges with these therapies.

Del nuevo producto biológico para el cáncer al impacto en la salud poblacional

La investigacion clinica no termina con el registro del nuevo medicamento, sino con la modificacion de los indicadores de salud poblacional. Este articulo ilustra la experiencia de la biotecnologia cubana en el proposito de contribuir a la reduccion de la mortalidad por tumores malignos. En el control del cancer, la biotecnologia tiene cuatro espacios de impacto: el primero es en la prevencion primaria mediante vacunas profilacticas, el segundo, consiste en las tecnicas de diagnostico precoz, el tercero es la estratificacion de los pacientes mediante marcadores moleculares pronosticos o predictivos y el cuarto rol radica en el tratamiento de la enfermedad diseminada con vacunas terapeuticas y anticuerpos monoclonales que reconocen blancos especificos en los tumores. El uso de estas terapias ha traido consigo un cambio de paradigma del tratamiento del cancer. La experiencia cubana ha sido exitosa debido a la existencia de un sistema de salud con altos estandares basado en la cobertura completa y equidad de acceso, el desarrollo del nivel primario de atencion medica, centro de gravedad del sistema cubano y el desarrollo en las ultimas tres decadas de una industria biotecnologica nacional, innovadora y con capacidad productiva para cubrir las necesidades nacionales de productos y exportar. A pesar de los avances, quedan grandes retos tecnicos y metodologicos. La investigacion cientifica posregistro permitira trazar la estrategia para optimizar el impacto de los nuevos productos en la salud poblacional, encaminada a incrementar la esperanza de vida de los cubanos.