Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program.

BACKGROUND: CIGB-247 is a cancer therapeutic vaccine that uses as antigen a variant of human vascular endothelial growth factor (VEGF) mixed with the bacterially-derived adjuvant VSSP. CIGB-247 has been already evaluated in two phase I clinical trials (CENTAURO and CENTAURO-2), showing to be safe and immunogenic in advanced cancer patients selected under well-defined and controlled clinical conditions. Surviving patients were submitted to monthly re-immunizations and some of them showed objective clinical benefits. Based on these results, a compassionate use program (CUP) with CIGB-247 was initiated for patients that did not meet the strict entry criteria applied for the CENTAURO and CENTAURO-2 clinical trials, but could potentially benefit from the application of this cancer therapeutic vaccine. RESULTS: Polyclonal IgM, IgA and IgG antibodies specific for VEGF were detected by ELISA in serum samples from patients vaccinated with 400 µg of antigen combined with 200 µg of VSSP. Polyclonal antibody response showed no cross reactivity for other VEGF family member molecules like VEGF-C and VEGF-D. Serum from immunized individuals was able to block the binding of VEGF to its receptors VEGFR2 and VEGFR1. IgG fraction purified from immune sera shared the aforementioned characteristics and also inhibited the interaction between VEGF and the therapeutic recombinant antibody bevacizumab, an anti-angiogenic drug approved for the treatment of different tumors. No serious adverse events attributable to CIGB-247 have been documented yet in participants of the CIGB-247 CUP. The present paper is a first report of our findings concerning the humoral response and safety characteristics in treated CIGB-247 CUP cancer patients. The study has provided the unique opportunity of not only testing CIGB-247 in a broader clinical spectrum sample of Cuban cancer patients, but also within the context of the day-to-day clinical practice and treatment settings for these diseases in Cuban medical institutions. CONCLUSIONS: The CIGB-247 CUP has demonstrated that immunization and follow-up of a variety of cancer patients, under day-to-day clinical practice conditions in several Cuban medical institutions, replicate our previous findings in clinical trials: CIGB-247 is safe and immunogenic.

Evaluation of methodologies to determine the effect of specific active immunotherapy on VEGF levels in phase I clinical trial patients with advanced solid tumors.

Two phase I clinical trials were conducted to evaluate, among other parameters, the humoral response elicited by a vascular endothelial growth factor (VEGF)-based therapeutic vaccine in cancer patients with advanced solid tumors. VEGF reduction was studied using an indirect methodology named as "Platelet VEGF". This methodology is based on the estimation of VEGF within platelets by subtracting the plasma VEGF level from the serum level and dividing this by the platelet count, and then this latter expression is additionally corrected by the hematocrit. However, there is broad debate, whether serum or plasma VEGF or platelet-derived VEGF measurements is the most appropriate strategy to study the changes that occur on ligand bioavailability when patients are submitted to a VEGF-based immunotherapy. The current research is a retrospective study evaluating the changes on VEGF levels in serum and plasma as well as platelet-derived measurements. Changes in VEGF levels were related with the humoral response seen in cancer patients after an active immunotherapy with a VEGF-based vaccine. The present study indicates that "Platelet VEGF" is the most reliable methodology to investigate the effect of VEGF-based immunotherapies on ligand bioavailability. "Platelet VEGF" was associated with those groups of individuals that exhibited the best specific humoral response and the variation of "Platelet VEGF" showed the strongest negative correlation with VEGF-specific IgG antibody levels. This methodology will be very useful for the investigation of this VEGF-based vaccine in phase II clinical trials and could be applied to immunotherapies directed to other growth factors that are actively sequestered by platelets.

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants.

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/ .

Análisis crítico de un control de foco VIH-SIDA en un municipio de la capital cubana / Critical analysis of a control of HIV/AIDS focus in a municipality of the cuban capital

Objetivo: realizar el análisis crítico a un control de foco VIH-SIDA, seleccionado aleatoriamente en un municipio de la capital cubana en el año 2005. Desarrollo: se revisó la documentación generada y disponible del caso en cuestión, y se entrevistaron a diferentes autoridades del área de salud, vinculados al cumplimiento del Programa de Control y Prevención VIH/SIDA. Conclusiones: se encontraron deficiencias en el cumplimiento del Programa Nacional de Control y Prevención del VIH/SIDA, que constituye una herramienta técnico-metodológica de incalculable valor para el control y prevención de esta enfermedad en el país, entre ellas, la no adhesión al Programa Nacional, el control inadecuado del mismo y la falta de exigencia en su cumplimiento por parte de las autoridades de salud del territorio.

Objetive: to make a critical analysis of a control of HIV/AIDS focus, selected at random in a municipality of the Cuban capital in 2005. Development: the generated and available documentation of the case was reviewed, and different authorities of the health area linked to the fulfilment of the HIV/AIDS Control and Prevention Program were interviewed. Conclusions: the non-adhesion to the National Program, its inadequate control and the lack of demand to fulfil it on the part of the health authorities of the territory, were some of the deficiencies detected that made difficult the accomplishment of the National HIV/AIDS Control and Prevention Program, which is a technical and methodological tool of great value for preventing and controlling this disease in the country.

Análisis crítico de un control de foco VIH-SIDA en un municipio de la capital cubana / Critical analysis of a control of HIV/AIDS focus in a municipality of the cuban capital

Objetivo: realizar el análisis crítico a un control de foco VIH-SIDA, seleccionado aleatoriamente en un municipio de la capital cubana en el año 2005. Desarrollo: se revisó la documentación generada y disponible del caso en cuestión, y se entrevistaron a diferentes autoridades del área de salud, vinculados al cumplimiento del Programa de Control y Prevención VIH/SIDA. Conclusiones: se encontraron deficiencias en el cumplimiento del Programa Nacional de Control y Prevención del VIH/SIDA, que constituye una herramienta técnico-metodológica de incalculable valor para el control y prevención de esta enfermedad en el país, entre ellas, la no adhesión al Programa Nacional, el control inadecuado del mismo y la falta de exigencia en su cumplimiento por parte de las autoridades de salud del territorio(AU)

Objetive: to make a critical analysis of a control of HIV/AIDS focus, selected at random in a municipality of the Cuban capital in 2005. Development: the generated and available documentation of the case was reviewed, and different authorities of the health area linked to the fulfilment of the HIV/AIDS Control and Prevention Program were interviewed. Conclusions: the non-adhesion to the National Program, its inadequate control and the lack of demand to fulfil it on the part of the health authorities of the territory, were some of the deficiencies detected that made difficult the accomplishment of the National HIV/AIDS Control and Prevention Program, which is a technical and methodological tool of great value for preventing and controlling this disease in the country(AU)