Survival of NSCLC Patients Treated with Cimavax-EGF as Switch Maintenance in the Real-World Scenario.

Introduction: In Cuba, lung cancer represents the first cause of mortality for both sexes. Non-small cell lung cancer (NSCLC) is the most prevalent histology. Overall, 75-85% of NSCLC overexpress EGFR and its ligands. EGFR overexpression has been implicated in the malignant transformation by promoting cell proliferation and survival. CIMAvax-EGF is a therapeutic vaccine composed of recombinant-human EGF conjugated to a carrier protein and Montanide as an adjuvant. CIMAvax-EGF is intended to induce antibodies against self-EGF that block the EGF-EGFR interaction. Objectives: To characterize the efficacy and safety of CIMAvax-EGF as maintenance in NSCLC patients treated in the real-world setting. Results: 106 patients diagnosed with advanced NSCLC at the National Institute of Oncology and Radiobiology, who had at least stable disease after first-line therapy, were enrolled in the study. The initial four CIMAvax-EGF doses were administered every 2 weeks and then, patients received monthly re-immunizations. Globally, 52.8% of the patients were 65 years or older, 77.4% had an ECOG 1 and 62.3% had an adenocarcinoma. The median survival time (MST) was 14.6 months. Patients younger than 65 years had a MST of 16.7 months and subjects with ECOG 0 survived for 29 months. The median progression-free survival was 8.16 months. Overall, 36.8% and 19.8% of patients maintained disease control at 6 and 12 months, respectively. The most frequent adverse events were pain (27.3%) or induration (7.3%) at the injection site and local erythema (10.9%). Conclusion: CIMAvax-EGF, as an EGF depleting immunotherapy used as switch-maintenance was safe and effective in patients with NSCLC.

Safety and effectiveness of CIMAvax-EGF administered in community polyclinics.

In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients' burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition. Clinical trial registration: https://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205.

Thymic Polypeptide Fraction Biomodulina T Decreases Exhausted and Terminally Differentiated EMRA T Cells in Advanced Lung Cancer Patients Treated With Platinum-Based Chemotherapy.

Lung cancer is the second cause of cancer related deaths worldwide. Chemotherapy and immunotherapy represent the current standard of care for advanced NSCLC. Platinum-based chemotherapy expands late-differentiated T cell populations. Therefore, immune restoration after chemotherapy to adjuvate the immunotherapeutic potential could be crucial. The aim of this study was to evaluate the effect of Biomodulina T (BT), a thymic polypeptide fraction, on peripheral lymphocytes subpopulations in the context of cancer disease. Additionally, whether these effects might induce a better response to CIMAvax-EGF, an epidermal growth factor (EGF) depleting immunotherapy. Eighteen advanced NSCLC patients were evaluated after being treated with platinum-based chemotherapy. We found that the frequency of terminally differentiated effector T cells re-expressing CD45RA (EMRA) CD4+ (p=0.0031) and CD8+ (p=0.0372) T cells decreased with the administration of BT, whereas CD4+ naive T cells increase in more than 70% of the patients. Remarkably, CD4+ and CD8+ T lymphocytes expressing programmed cell death receptor-1 (PD1) significantly decreased after BT administration (p=0.0005 and p<0.0001, respectively). We also found an enhancement of the anti-EGF antibody response with a large percentage of patients treated with CIMAvax-EGF reaching the good antibody response condition after four vaccine doses. Moreover, the median overall survival of patients treated with CIMAvax-EGF was 16.09 months. In conclusion, our results suggest that the immunorestoration generated by the administration of BT after first-line chemotherapy may induce a better immune response to CIMAvax-EGF that could translate into the clinical benefit of patients diagnosed with advanced NSCLC.

The Position of EGF Deprivation in the Management of Advanced Non-Small Cell Lung Cancer.

Advanced non-small cell lung cancer (NSCLC) has faced a therapeutic revolution with the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoints inhibitors (ICIs) approved for first and subsequent therapies. CIMAvax-EGF is a chemical conjugate between human-recombinant EGF and P64, a recombinant protein from Neisseria meningitides, which induces neutralizing antibodies against EGF. In the last 15 years, it has been extensively evaluated in advanced NSCLC patients. CIMAvax-EGF is safe, even after extended use, and able to keep EGF serum concentration below detectable levels. In a randomized phase III study, CIMAvax-EGF increased median overall survival of advanced NSCLC patients with at least stable disease after front-line chemotherapy. Patients bearing squamous-cell or adenocarcinomas and serum EGF concentration above 870 pg/ml had better survival compared to control patients treated with best supportive care as maintenance, confirming tumors' sensitivity to the EGF depletion. This manuscript reviews the state-of-the-art NSCLC therapy and proposes the most promising scenarios for evaluating CIMAvax-EGF, particularly in combination with TKIs or ICIs. We hypothesize that the optimal combination of CIMAvax-EGF with established therapies can further contribute to transform advanced cancer into a manageable chronic disease, compatible with years of good quality of life.

Uso de la vacuna CIMAvax-EGF® como práctica médica habitual / Use of the vaccine CIMAvax-EGF® as habitual medical practice

Se realizó un estudio descriptivo y longitudinal de 58 pacientes con cáncer de pulmón de células no pequeñas, atendidos en la consulta de Sombras Pulmonares correspondiente al Servicio de Neumología del Hospital General Docente Dr Juan Bruno Zayas Alfonso de Santiago de Cuba, desde enero del 2013 hasta igual mes del 2018, quienes eran tratados con CIMAvax-EGF® como práctica médica habitual, con vistas a determinar las características clinicoepidemiológicas de estos. En la serie primaron el sexo masculino y las edades de 60 a 79 años; asimismo, resultaron más frecuentes la etapa IV de la enfermedad y el adenocarcinoma como variedad histológica. Con el uso de la vacuna la mayoría de los pacientes presentaron una supervivencia de 12,9 meses y una respuesta terapéutica de enfermedad no progresora

A descriptive and longitudinal study of 58 patients with lung cancer of non small cells, assisted in the service of Lung Shades corresponding to the Pneumology Service of Dr Juan Bruno Zayas Alfonso Teaching General Hospital was carried out in Santiago de Cuba, from January, 2013 to the same month of 2018, who were treated with CIMAvax-EGF® as habitual medical practice, with the aim of determining the clinical and epidemiological characteristics of them. The male sex and ages from 60 to 79 years prevailed in the series; also, stage IV of the disease and the adenocarcinoma as histological variety were more frequent. With the use of the vaccine most of the patients presented a survival of 12.9 months and a therapeutic response of the non progressive disease

CIMAvax-EGF: Toward long-term survival of advanced NSCLC.

Lung cancer remains one of the leading causes of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common histologic type of lung cancer. Medical and scientific progress has led to longer survival in an increasing number of patients suffering from cancer. Concerning patients with advanced NSCLC, there is a subgroup with long-term survival. The human epidermal growth factor receptor (EGFR) family plays a key role in tumor development. This cluster of genes is associated with augmented angiogenesis and enhanced proliferation, survival, and migration of tumor cells. The CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and the Montanide ISA 51, as adjuvant. The vaccine induces antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF has been demonstrated to be safe and immunogenic in advanced NSCLC patients. Here we summarize the current knowledge of the mechanism of action of CIMAvax-EGF, highlighting the impact of this anti-EGF-based vaccine on the long-term survival of advanced NSCLC patients.

CIMAvax-EGF, a therapeutic non-small cell lung cancer vaccine.

INTRODUCTION: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy. The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction. Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials. Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.

CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients.

Lung cancer is the common fatal illness with the highest incidence and mortality globally. Epidermal growth factor receptor overexpression by tumor cells is associated with uncontrolled proliferation, angiogenesis, anti-apoptotic signals, metastization, and invasiveness. CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and Montanide ISA 51, as adjuvant. The vaccine is projected to induce antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF demonstrated to be safe and immunogenic in advanced non-small cell lung cancer (NSCLC) patients. The efficacy study was an open-label, multicentric Phase III clinical trial, which enrolled 405 advanced NSCLC patients. Patients with proven stage IIIB/IV NSCLC, who had completed four to six cycles of chemotherapy (CTP) were randomized to receive CIMAvax-EGF or best supportive care. CIMAvax-EGF resulted in a significantly larger overall survival in patients receiving at least four doses. High EGF concentration at baseline was a good predictive biomarker of the vaccine activity and a poor prognostic biomarker for the non-treated population. The proportion of CD8+CD28- cells, CD4 cells, and the CD4/CD8 ratio after first-line CTP was also associated with CIMAvax-EGF clinical benefit. After completing the Phase III, a Phase IV trial was done where the vaccine was administered in primary care units. Administering the vaccine at primary care institutions granted better access and treatment compliance. Safety was confirmed. Several clinical trials are currently ongoing to validate EGF as a predictive biomarker of CIMAvax-EGF efficacy.

Aplicación de productos inmunoterapéuticos en ensayos clínicos oncológicos en Santiago de Cuba / Implementation of immunotherapeutical products in cancer clinical trials in Santiago de Cuba

Se realizó un estudio descriptivo y retrospectivo sobre la conducción de ensayos clínicos durante 23 años en Santiago de Cuba, con el objetivo de describir la aplicación de 3 productos inmunoterapéuticos (CIMAher-Nimotuzumab, CIMAvax-EGF y Vaxira-Racotumomab) para el tratamiento de pacientes con cáncer en hospitales y policlínicos de la provincia. Se revisaron los informes finales de dichos ensayos, así como la información disponible del centro promotor desde 1992 hasta 2015. Se ejecutaron 20 protocolos de ensayos clínicos por 500 investigadores de 25 especialidades, distribuidos en 4 hospitales de la provincia y 2 se extendieron a 4 áreas de atención primaria de salud. Se concluyó que la aplicación de estos productos inmunoterapéuticos contribuyó al registro sanitario de estos, lo cual enriqueció el arsenal terapéutico para los afectados por cáncer en Santiago de Cuba, con un elevado impacto social(AU)

A retrospective descriptive study on the presentation of clinical trials was carried out during 23 years in Santiago de Cuba, with the objective of describing the implementation of 3 immunotherapeutical products (CIMAher-Nimotuzumab, CIMAvax-EGF and Vaxira-Racotumomab) for the treatment of patients with cancer in hospitals and polyclinics from the province. The final reports of each clinical trial and the available information of the promoter center were reviewed from 1992 to 2015. Twenty protocols of clinical trials were implemented by 500 investigators of 25 specialties distributed in 4 hospitals of the province and 4 primary health care areas, where 2 clinical trials in patients with lung cancer were carried out. It was concluded that the implementation of these immunotherapeutical products contributed to the health registration of them, enriching the therapeutic arsenal for the treatment of patients with cancer in Santiago de Cuba, with a high social impact(AU)

Aplicación de productos inmunoterapéuticos en ensayos clínicos oncológicos en Santiago de Cuba / Implementation of immunotherapeutical products in cancer clinical trials in Santiago de Cuba

Se realizó un estudio descriptivo y retrospectivo sobre la conducción de ensayos clínicos durante 23 años en Santiago de Cuba, con el objetivo de describir la aplicación de 3 productos inmunoterapéuticos (CIMAher-Nimotuzumab, CIMAvax-EGF y Vaxira-Racotumomab) para el tratamiento de pacientes con cáncer en hospitales y policlínicos de la provincia. Se revisaron los informes finales de dichos ensayos, así como la información disponible del centro promotor desde 1992 hasta 2015. Se ejecutaron 20 protocolos de ensayos clínicos por 500 investigadores de 25 especialidades, distribuidos en 4 hospitales de la provincia y 2 se extendieron a 4 áreas de atención primaria de salud. Se concluyó que la aplicación de estos productos inmunoterapéuticos contribuyó al registro sanitario de estos, lo cual enriqueció el arsenal terapéutico para los afectados por cáncer en Santiago de Cuba, con un elevado impacto social

A retrospective descriptive study on the presentation of clinical trials was carried out during 23 years in Santiago de Cuba, with the objective of describing the implementation of 3 immunotherapeutical products (CIMAher-Nimotuzumab, CIMAvax-EGF and Vaxira-Racotumomab) for the treatment of patients with cancer in hospitals and polyclinics from the province. The final reports of each clinical trial and the available information of the promoter center were reviewed from 1992 to 2015. Twenty protocols of clinical trials were implemented by 500 investigators of 25 specialties distributed in 4 hospitals of the province and 4 primary health care areas, where 2 clinical trials in patients with lung cancer were carried out. It was concluded that the implementation of these immunotherapeutical products contributed to the health registration of them, enriching the therapeutic arsenal for the treatment of patients with cancer in Santiago de Cuba, with a high social impact

An enzyme immunoassay for determining epidermal growth factor (EGF) in human serum samples using an ultramicroanalytical system.

Human epidermal growth factor is a small peptide consisting of 53 amino acid residues, which stimulates cell proliferation and is associated with several human carcinomas. A simple sandwich-type ultramicroELISA assay (UMELISA), based on the advantages of high affinity reaction between streptavidin and biotin has been developed for the measurement of EGF in human serum samples. Strips coated with a high affinity monoclonal antibody directed against EGF are used as solid phase, to ensure the specificity of the assay. The EGF assay was completed in 18 hr, with a measuring range of 39-2500 pg/mL. The intra- and inter-assay coefficients of variation were 4.4-7.3% and 0-5.1%, respectively, depending on the EGF concentrations evaluated. Percentage recovery ranged from 96-104%. Regression analysis showed a good correlation with the commercially available Human EGF Immunoassay Quantikine® ELISA kit (n = 130, r = 0.92, P < 0.01). The analytical performance characteristics of our UMELISA EGF endorse its use for the quantification of EGF in human serum samples.

Supervivencia en pacientes con cáncer pulmonar de células no pequeñas vacunados con CIMAvax-EGF / Survival in patients with non-small cell lung cancer vaccinated with CIMAvax-EGF

Se realizó un estudio observacional, descriptivo y longitudinal en un primer momento, y analítico de cohorte en un segundo tiempo, de 95 pacientes con cáncer de pulmón de células no pequeñas en estadios avanzados, asistidos en el Hospital Provincial Docente Clinicoquirúrgico Saturnino Lora Torres y en 4 policlínicos de la ciudad de Santiago de Cuba, durante el período 2006-2013, a fin de estimar la supervivencia en ellos luego de la vacunación con CIMAvax-EGF e identificar los factores asociados a la mortalidad, para lo cual se empleó el método de Kaplan-Meier y el de regresión de Cox, respectivamente. La supervivencia global a los 2 años fue de 20,7 por ciento, con una mediana de 13 meses, en tanto la supervivencia al año de aplicada la vacuna fue de 36,5 por ciento. Por su parte, el estadio IIIB, la respuesta favorable a la primera línea de tratamiento, la combinación quimioterapia-radioterapia-vacuna y la inmunización en 4 o más ocasiones, posibilitaron una supervivencia significativamente mayor. La reacción desfavorable a la primera línea terapéutica constituyó un factor pronóstico del incremento del riesgo de muerte en la población de afectados(AU)

An observational, descriptive and cross-sectional study in a first moment, and cohort analytic in a second time, of 95 patients with non-small cell lung cancer in advanced stages, assisted at "Saturnino Lora Torres" Teaching Clinical Surgical Provincial Hospital and in 4 polyclinics of Santiago de Cuba, was carried out during the period 2006-2013, in order to estimate the survival in them after the vaccination with CIMAvax-EGF and to identify the factors associated to the mortality, for which Kaplan-Meier method and Cox regression were used, respectively. The global survival in 2 years was 20.7 percent, with a median of 13 months, as long as the survival a year after applying the vaccine was 36.5 percent. On the other hand, in the stage IIIB, the favorable response to the first line treatment, the chemotherapy-radiotherapy-vaccine combination and the immunization in 4 or more occasions, facilitated a significantly higher survival. The unfavorable reaction to the first therapeutic line constituted a prediction factor of death risk increase in the population affected(AU)

Supervivencia en pacientes con cáncer pulmonar de células no pequeñas vacunados con CIMAvax-EGF / Survival in patients with non-small cell lung cancer vaccinated with CIMAvax-EGF

Se realizó un estudio observacional, descriptivo y longitudinal en un primer momento, y analítico de cohorte en un segundo tiempo, de 95 pacientes con cáncer de pulmón de células no pequeñas en estadios avanzados, asistidos en el Hospital Provincial Docente Clinicoquirúrgico "Saturnino Lora Torres" y en 4 policlínicos de la ciudad de Santiago de Cuba, durante el período 2006-2013, a fin de estimar la supervivencia en ellos luego de la vacunación con CIMAvax-EGF e identificar los factores asociados a la mortalidad, para lo cual se empleó el método de Kaplan-Meier y el de regresión de Cox, respectivamente. La supervivencia global a los 2 años fue de 20,7 %, con una mediana de 13 meses, en tanto la supervivencia al año de aplicada la vacuna fue de 36,5 %. Por su parte, el estadio IIIB, la respuesta favorable a la primera línea de tratamiento, la combinación quimioterapia-radioterapia-vacuna y la inmunización en 4 o más ocasiones, posibilitaron una supervivencia significativamente mayor. La reacción desfavorable a la primera línea terapéutica constituyó un factor pronóstico del incremento del riesgo de muerte en la población de afectados.

An observational, descriptive and cross-sectional study in a first moment, and cohort analytic in a second time, of 95 patients with non-small cell lung cancer in advanced stages, assisted at "Saturnino Lora Torres" Teaching Clinical Surgical Provincial Hospital and in 4 polyclinics of Santiago de Cuba, was carried out during the period 2006-2013, in order to estimate the survival in them after the vaccination with CIMAvax-EGF and to identify the factors associated to the mortality, for which Kaplan-Meier method and Cox regression were used, respectively. The global survival in 2 years was 20.7%, with a median of 13 months, as long as the survival a year after applying the vaccine was 36.5%. On the other hand, in the stage IIIB, the favorable response to the first line treatment, the chemotherapy-radiotherapy-vaccine combination and the immunization in 4 or more occasions, facilitated a significantly higher survival. The unfavorable reaction to the first therapeutic line constituted a prediction factor of death risk increase in the population affected.

Supervivencia libre de progresión de cáncer pulmonar de células no pequeñas en pacientes vacunados con CIMAvax-EGF / Progression-free survival of non-small cells lung cancer in patients vaccinated with CIMAvax-EGF

Se efectuó un estudio observacional, descriptivo y longitudinal durante un primer momento, y analítico de cohorte en un segundo tiempo, de 95 pacientes con cáncer de pulmón de células no pequeñas en estadios avanzados (IIIB-IV) y de los subtipos histológicos carcinoma epidermoide y adenocarcinoma, quienes fueron tratados con la vacuna CIMAvax-EGF en el Departamento de Ensayos Clínicos del Hospital Provincial Docente Clinicoquirúrgico Saturnino Lora Torres, y en los policlínicos 30 de Noviembre, 28 de Septiembre, José Martí y Camilo Torres de la provincia de Santiago de Cuba, en el período 2006-2013, a fin de estimar la supervivencia libre de progresión de la entidad clínica en ellos. Pasado un año de la vacunación, la probabilidad de supervivencia libre de progresión fue solo de 30,5 por ciento, la cual resultó significativamente superior en los afectados en estadio IIIB, con una respuesta favorable a la primera línea de tratamiento, luego de haber recibido la combinación de quimioterapia con radioterapia y vacuna CIMAvax-EGF, siempre que se emplearon 4 o más inmunizaciones(AU)

An observational, descriptive and longitudinal study during a first time, and analytic case-control study in a second time, of 95 patients with non small cells lung cancer, in advanced stages (IIIB-IV) and of the epidermoid carcinoma and adenocarcinoma histological subtypes who were treated with the vaccine CIMAvax-EGF in the Department of Clinical Assays of Saturnine Lora Torres Teaching Clinical Surgical Provincial Hospital, and in 30 de Noviembre, 28 de Septiembre, José Martí and Camilo Torres polyclinics in Santiago de Cuba province, was carried out in the period 2006-2013, in order to estimate the progression-free survival of the clinical entity in them. After a year of the vaccination, the probability of progression-free survival was just 30.5 percent, which was significantly higher in stage IIIB patients, with a favourable response to the first treatment line, after treated with a chemotherapy-radiotherapy combination and bovine CIMAvax-EGF, whenever 4 or more immunizations were used(AU)

Supervivencia libre de progresión de cáncer pulmonar de células no pequeñas en pacientes vacunados con CIMAvax-EGF / Progression-free survival of non-small cells lung cancer in patients vaccinated with CIMAvax-EGF

Se efectuó un estudio observacional, descriptivo y longitudinal durante un primer momento, y analítico de cohorte en un segundo tiempo, de 95 pacientes con cáncer de pulmón de células no pequeñas en estadios avanzados (IIIB-IV) y de los subtipos histológicos carcinoma epidermoide y adenocarcinoma, quienes fueron tratados con la vacuna CIMAvax-EGF en el Departamento de Ensayos Clínicos del Hospital Provincial Docente Clinicoquirúrgico “Saturnino Lora Torres”, y en los policlínicos “30 de Noviembre”, “28 de Septiembre”, “José Martí” y “Camilo Torres” de la provincia de Santiago de Cuba, en el período 2006-2013, a fin de estimar la supervivencia libre de progresión de la entidad clínica en ellos. Pasado un año de la vacunación, la probabilidad de supervivencia libre de progresión fue solo de 30,5 %, la cual resultó significativamente superior en los afectados en estadio IIIB, con una respuesta favorable a la primera línea de tratamiento, luego de haber recibido la combinación de quimioterapia con radioterapia y vacuna CIMAvax-EGF, siempre que se emplearon 4 o más inmunizaciones.

An observational, descriptive and longitudinal study during a first time, and analytic case-control study in a second time, of 95 patients with non small cells lung cancer, in advanced stages (IIIB-IV) and of the epidermoid carcinoma and adenocarcinoma histological subtypes who were treated with the vaccine CIMAvax-EGF in the Department of Clinical Assays of “Saturnine Lora Torres” Teaching Clinical Surgical Provincial Hospital, and in “30 de Noviembre”, “28 de Septiembre”, “José Martí” and “Camilo Torres” polyclinics in Santiago de Cuba province, was carried out in the period 2006-2013, in order to estimate the progression-free survival of the clinical entity in them. After a year of the vaccination, the probability of progression-free survival was just 30.5%, which was significantly higher in stage IIIB patients, with a favourable response to the first treatment line, after treated with a chemotherapy-radiotherapy combination and bovine CIMAvax-EGF, whenever 4 or more immunizations were used.

Efectos del bloqueo del sistema EGF/EGFR sobre la cicatrización de las heridas en pacientes oncológicos / Effects of the blockade of EGF/EGFR system on wound healing cancer patients

La administración de drogas que bloquean el sistema del factor de crecimiento epidérmico y su receptor ha demostrado efectos beneficiosos en pacientes con tumores sólidos de origen epitelial. Cada día resulta más frecuente el uso de múltiples modalidades terapéuticas para combatir estos tumores, las cuales incluyen la asociación de agentes blanco y cirugía. Los agentes que actúan sobre dicho sistema pudieran causar trastornos de la cicatrización al bloquear vías del sistema que también intervienen en la cicatrización de las heridas. El objetivo de este artículo es revisar y comentar acerca del conocimiento de la relación entre el uso de las drogas anti-EGF/EGFR y los trastornos en la cicatrización de las heridas. La búsqueda bibliográfica se realizó en PubMed y Google (solo en español e inglés) y se tuvo en cuenta cualquier publicación encontrada hasta enero del 2014. Se incluyeron los anticuerpos monoclonales cetuximab, panitumumab y nimotuzumab; las pequeñas moléculas erlotinib y gefitinib y las vacunas terapéuticas contra el cáncer CIMAvax EGF y HER-1. Se hace especial énfasis en los biofarmacéuticos nimotuzumab, CIMAvax EGF y HER-1; producidos en el Centro de Inmunología Molecular, La Habana, Cuba, debido a su amplio uso en Cuba y otros países de América Latina. No se encontraron evidencias de relación entre el uso de estos productos y la aparición de trastornos en la cicatrización de las heridas. Dado que los tratamientos anti-EGF/EGFR también inhiben la proliferación celular que induce el drenaje de las heridas y la migración celular inducida por las radiaciones, se sugiere que el tratamiento anti-EGF/EGFR no debe suspenderse, ni antes ni después de la cirugía y sus posibles efectos deben ser vigilados. Obviamente, se necesitan ulteriores investigaciones por parte de los farmacólogos no clínicos y clínicos, oncólogos clínicos y cirujanos oncológicos para entender mejor los procesos fisiopatológicos de cicatrización en los cánceres de origen epitelial(AU)

The use of blocking drugs for epidermal growth factor and its receptor system has shown beneficial effects in patients with solid tumors of epithelial origin. It is increasingly common to use a multi-modal treatment approach towards solid tumors, often including the association of target agents and surgical resection. Some target agents can impair wound healing or cause increasing risk of perioperative complications if they block system pathways that may intervene in wound healing. The objective of this paper was to review and comment on the existing knowledge about the relationship between the use of anti-EGF/EGFR drugs and the disorders in wound healing. Citations from PubMed and Google (English and Spanish languages only) regardless of the date of publication were reviewed to identify potentially useful articles until January 2014. Monoclonal antibodies cetuximab, panitumumab, nimotuzumab; the small molecules erlotinib and gefitinib, and the therapeutic cancer vaccines called CIMAvax EGF and HER-1. Special emphasis was made on biopharmaceuticals nimotuzumab, CIMAvax EGF and HER-1, all of them produced at the Center of Molecular Immunology, Havana, Cuba, because of their extensive use in Cuba and many Latin-American countries. No evidence of association between the use of these products and the occurrence of complications in wound healing was found. Given that the anti-EGF/EGFR treatments also inhibit the tumor cell proliferation that wound drainage induces and the radiation-induced cell migration, it is suggested that that the administration of this kind of drugs should be kept before and after the surgery and consequently, its possible effects must be under surveillance. Obviously, non-clinical and clinical pharmacologists, clinical oncologists and surgeons need further researches for better understanding the pathophysiological wound healing processes in epithelial cancers(AU)

Efectos del bloqueo del sistema EGF/EGFR sobre la cicatrización de las heridas en pacientes oncológicos / Effects of the blockade of EGF/EGFR system on wound healing cancer patients

La administración de drogas que bloquean el sistema del factor de crecimiento epidérmico y su receptor ha demostrado efectos beneficiosos en pacientes con tumores sólidos de origen epitelial. Cada día resulta más frecuente el uso de múltiples modalidades terapéuticas para combatir estos tumores, las cuales incluyen la asociación de agentes blanco y cirugía. Los agentes que actúan sobre dicho sistema pudieran causar trastornos de la cicatrización al bloquear vías del sistema que también intervienen en la cicatrización de las heridas. El objetivo de este artículo es revisar y comentar acerca del conocimiento de la relación entre el uso de las drogas anti-EGF/EGFR y los trastornos en la cicatrización de las heridas. La búsqueda bibliográfica se realizó en PubMed y Google (solo en español e inglés) y se tuvo en cuenta cualquier publicación encontrada hasta enero del 2014. Se incluyeron los anticuerpos monoclonales cetuximab, panitumumab y nimotuzumab; las pequeñas moléculas erlotinib y gefitinib y las vacunas terapéuticas contra el cáncer CIMAvax EGF y HER-1. Se hace especial énfasis en los biofarmacéuticos nimotuzumab, CIMAvax EGF y HER-1; producidos en el Centro de Inmunología Molecular, La Habana, Cuba, debido a su amplio uso en Cuba y otros países de América Latina. No se encontraron evidencias de relación entre el uso de estos productos y la aparición de trastornos en la cicatrización de las heridas. Dado que los tratamientos anti-EGF/EGFR también inhiben la proliferación celular que induce el drenaje de las heridas y la migración celular inducida por las radiaciones, se sugiere que el tratamiento anti-EGF/EGFR no debe suspenderse, ni antes ni después de la cirugía y sus posibles efectos deben ser vigilados. Obviamente, se necesitan ulteriores investigaciones por parte de los farmacólogos no clínicos y clínicos, oncólogos clínicos y cirujanos oncológicos para entender mejor los procesos fisiopatológicos de cicatrización en los cánceres de origen epitelial(AU)

The use of blocking drugs for epidermal growth factor and its receptor system has shown beneficial effects in patients with solid tumors of epithelial origin. It is increasingly common to use a multi-modal treatment approach towards solid tumors, often including the association of target agents and surgical resection. Some target agents can impair wound healing or cause increasing risk of perioperative complications if they block system pathways that may intervene in wound healing. The objective of this paper was to review and comment on the existing knowledge about the relationship between the use of anti-EGF/EGFR drugs and the disorders in wound healing. Citations from PubMed and Google (English and Spanish languages only) regardless of the date of publication were reviewed to identify potentially useful articles until January 2014. Monoclonal antibodies cetuximab, panitumumab, nimotuzumab; the small molecules erlotinib and gefitinib, and the therapeutic cancer vaccines called CIMAvax EGF and HER-1. Special emphasis was made on biopharmaceuticals nimotuzumab, CIMAvax EGF and HER-1, all of them produced at the Center of Molecular Immunology, Havana, Cuba, because of their extensive use in Cuba and many Latin-American countries. No evidence of association between the use of these products and the occurrence of complications in wound healing was found. Given that the anti-EGF/EGFR treatments also inhibit the tumor cell proliferation that wound drainage induces and the radiation-induced cell migration, it is suggested that that the administration of this kind of drugs should be kept before and after the surgery and consequently, its possible effects must be under surveillance. Obviously, non-clinical and clinical pharmacologists, clinical oncologists and surgeons need further researches for better understanding the pathophysiological wound healing processes in epithelial cancers(AU)

Del nuevo producto biológico para el cáncer al impacto en la salud poblacional / From the new biologic cancer drug to the impact in population health

La investigación clínica no termina con el registro del nuevo medicamento, sino con la modificación de los indicadores de salud poblacional. Este artículo ilustra la experiencia de la biotecnología cubana en el propósito de contribuir a la reducción de la mortalidad por tumores malignos. En el control del cáncer, la biotecnología tiene cuatro espacios de impacto: el primero es en la prevención primaria mediante vacunas profilácticas, el segundo, consiste en las técnicas de diagnóstico precoz, el tercero es la estratificación de los pacientes mediante marcadores moleculares pronósticos o predictivos y el cuarto rol radica en el tratamiento de la enfermedad diseminada con vacunas terapéuticas y anticuerpos monoclonales que reconocen blancos específicos en los tumores. El uso de estas terapias ha traído consigo un cambio de paradigma del tratamiento del cáncer. La experiencia cubana ha sido exitosa debido a la existencia de un sistema de salud con altos estándares basado en la cobertura completa y equidad de acceso, el desarrollo del nivel primario de atención médica, centro de gravedad del sistema cubano y el desarrollo en las últimas tres décadas de una industria biotecnológica nacional, innovadora y con capacidad productiva para cubrir las necesidades nacionales de productos y exportar. A pesar de los avances, quedan grandes retos técnicos y metodológicos. La investigación científica posregistro permitirá 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(AU)

The clinical research does not finish with the registration of a new drug, but with the modification of the population health indexes. This paper set forth the experience of the Cuban biotechnology in cancer control, in order to achieve the reduction of mortality rate from malignant tumors. Biotechnology has four areas of remarkable impact in cancer control: first, the primary prevention by means of prophylactic vaccines; second, the techniques for early diagnosis; third, the stratification of patients according to the molecular prognostic or predictive biomarkers and fourth, the treatment of advanced disseminated cancer with therapeutic cancer vaccines and monoclonal antibodies that detect specific targets in tumors. The use of these therapies has entailed a shift of paradigm in the cancer therapy. The Cuban experience has been successful due to the existence of a high standard health system based on complete coverage and equal access, the development of the primary medical care- the core of the Cuban health system -and the advance of a national, innovative biotech industry with manufacturing capacity to meet the national demand and to export products. In spite of the advances, big technical and methodological challenges still remain. Post-registration scientific research would define the strategy to optimize the impact of the new products in the population's health, aimed at increasing the life expectancy of the Cuban people(AU)

Del nuevo producto biológico para el cáncer al impacto en la salud poblacional / From the new biologic cancer drug to the impact in population health

La investigación clínica no termina con el registro del nuevo medicamento, sino con la modificación de los indicadores de salud poblacional. Este artículo ilustra la experiencia de la biotecnología cubana en el propósito de contribuir a la reducción de la mortalidad por tumores malignos. En el control del cáncer, la biotecnología tiene cuatro espacios de impacto: el primero es en la prevención primaria mediante vacunas profilácticas, el segundo, consiste en las técnicas de diagnóstico precoz, el tercero es la estratificación de los pacientes mediante marcadores moleculares pronósticos o predictivos y el cuarto rol radica en el tratamiento de la enfermedad diseminada con vacunas terapéuticas y anticuerpos monoclonales que reconocen blancos específicos en los tumores. El uso de estas terapias ha traído consigo un cambio de paradigma del tratamiento del cáncer. La experiencia cubana ha sido exitosa debido a la existencia de un sistema de salud con altos estándares basado en la cobertura completa y equidad de acceso, el desarrollo del nivel primario de atención médica, centro de gravedad del sistema cubano y el desarrollo en las últimas tres décadas de una industria biotecnológica nacional, innovadora y con capacidad productiva para cubrir las necesidades nacionales de productos y exportar. A pesar de los avances, quedan grandes retos técnicos y metodológicos. La investigación científica posregistro permitirá 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

The clinical research does not finish with the registration of a new drug, but with the modification of the population health indexes. This paper set forth the experience of the Cuban biotechnology in cancer control, in order to achieve the reduction of mortality rate from malignant tumors. Biotechnology has four areas of remarkable impact in cancer control: first, the primary prevention by means of prophylactic vaccines; second, the techniques for early diagnosis; third, the stratification of patients according to the molecular prognostic or predictive biomarkers and fourth, the treatment of advanced disseminated cancer with therapeutic cancer vaccines and monoclonal antibodies that detect specific targets in tumors. The use of these therapies has entailed a shift of paradigm in the cancer therapy. The Cuban experience has been successful due to the existence of a high standard health system based on complete coverage and equal access, the development of the primary medical care- the core of the Cuban health system -and the advance of a national, innovative biotech industry with manufacturing capacity to meet the national demand and to export products. In spite of the advances, big technical and methodological challenges still remain. Post-registration scientific research would define the strategy to optimize the impact of the new products in the population's health, aimed at increasing the life expectancy of the Cuban people