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IDIBELL (Instituto de Investigación Biomédica de Bellvitge)

IDIBELL (Instituto de Investigación Biomédica de Bellvitge)

Centro de investigación en medicina celular. El IDIBELL es un centro de investigación en medicina celular, donde la investigación básica de alto nivel está al servicio de preguntas clínicas relevantes y del desarrollo económico. El IDIBELL es una fundación creada el año 2004, a partir de la fusión de varias entidades de investigación, participado por el Hospital Universitario de Bellvitge, el Instituto Catalán de Oncología y la Universidad de Barcelona. El Instituto está situado en espacio Biopol'H. El año 2009 se convirtió en uno de los cinco primeros centros de investigación españoles acreditados como instituto de investigación sanitaria por el Instituto de Salud Carlos III. El Instituto de Investigación Biomédica de Bellvitge está situado en el municipio de L’Hospitalet de Llobregat, al sur de Barcelona. Sus instalaciones están distribuidas entre el Hospital Duran i Reynals, el Hospital Universitario de Bellvitge y los edificios del campus de la Universidad de Barcelona de Bellvitge, en el espacio Biopol. Un aspecto fundamental de la investigación del IDIBELL es su proximidad al enfermo. Por su situación y por la actividad asistencial diaria que muchos de ellos desarrollan, los investigadores del IDIBELL conocen los problemas que son realmente prioritarios y qué soluciones resultan efectivas en la práctica clínica diaria. Institut d'Investigació Biomédica de Bellvitge (IDIBELL). Hospital Duran i Reynals. 3a planta - Gran Via de l'Hospitalet, 199. 08908 Hospitalet de Llobregat. Barcelona - Spain. Tel +34 93 260 74 11. info@idibell.cat

Entrevista con el Dr. Ramón Alemany

Fuente: Excodra | Publicado: 04-03-2017
Otra personalización más extrema en fase de estudio consiste en fabricar un fármaco para cada paciente, analizando el tumor y dotando al virus o al fármaco de los elementos adecuados para ese tumor. Esta personalización extrema parece necesaria si queremos usar antígenos para inmunizar o vacunar al paciente frente a su tumor. Cada tumor presenta mutaciones distintas que generan antígenos distintos reconocibles por el sistema inmune del paciente.
Derechos: Dr. Ramón Alemany
22 comentarios

Ramón, para comenzar, a grandes rasgos, para ese campo de la medicina tan singular y apasionante que desarrolláis en vuestro laboratorio, ¿qué es y en qué se basa la viroterapia?


La viroterapia es el uso de virus para el tratamiento del cáncer. Los virus se pueden inyectar directamente en los tumores o en sangre, y cuando alcanzan e infectan las células tumorales se multiplican en su interior y las matan. El virus se va multiplicando hasta que elimina el tumor o hasta que el sistema inmune lo detiene. Pero la misma activación del sistema inmune en el tumor para eliminar el virus, puede servir para reactivar el sistema inmune contra el tumor, ya que los tumores desarrollan mecanismos para suprimir o escapar del sistema inmune.



La viroterapia es tan antigua como el propio descubrimiento de los virus, a principios del siglo pasado. Los médicos observaron muy ocasionalmente que tras infecciones virales o vacunaciones algunos pacientes con linfomas se curaban.


A partir de ahí se usaron muchos virus, pero su toxicidad y falta de eficacia llevó a abandonar esta estrategia en favor de la quimioterapia. Ahora el conocimiento de la biología viral y tumoral y las herramientas de manipulación genética nos permiten diseñar virus más selectivos, es decir que crecen  sólo en células tumorales y son menos tóxicos, y a la vez más potentes.

Luego, más en concreto, ¿qué son los adenovirus oncolíticos y cómo ha sido su evolución terapéutica hasta hoy? Y, ¿hay ya algún tipo de cáncer en humanos que se trate regularmente con adenovirus o aún no se ha pasado de los ensayos clínicos?

Los adenovirus (hay 55 tipos distintos que afectan a humanos) son virus comunes en la población que causan resfriados, conjuntivitis, o gastroenteritis que pueden suponer un riesgo para algunas personas con un sistema inmune muy deficiente. Los adenovirus oncolíticos son adenovirus que se han modificado genéticamente, generalmente eliminando algunos de sus genes, para multiplicarse sólo en células tumorales.



También pueden contener modificaciones que los hacen más potentes frente al tumor, como genes activadores del sistema inmune. En ensayos clínicos frente a distintos tipos de tumores han mostrado poca eficacia y sólo en China se ha aprobado el uso comercial de un adenovirus oncolítico llamado Oncorine que se inyecta directamente en distintos tipos de tumores.


En Europa y EEUU nuevos adenovirus oncolitícos están en fases de investigación clínica, y la reciente aprobación de un herpesvirus oncolítico para el melanoma por inyección repetida intratumoral ha reactivado el interés de la farmaindustria en los virus oncolíticos en general, sobre todo como activadores del sistema inmune contra el tumor. 

¿Cuáles son las limitaciones actuales por superar para que mediante el uso de virus oncolíticos pudiera tratarse el cáncer de manera efectiva?

Son tres. Primero la llegada del virus a los focos tumorales o metástasis diseminadas por el organismo. Necesitamos que más cantidad de virus llegue a los tumores por vía sanguínea, ya que la inyección directa de tumores presenta limitaciones técnicas para detectar e inyectar todas las metástasis. En segundo lugar, los tumores tienen barreras físicas de tejido conectivo, el llamado estroma tumoral, que el virus no puede atravesar. Finalmente, debemos conseguir que la respuesta inmune que se activa frente al virus y lo elimina del tumor, también sea capaz de eliminar células tumorales que no han sido infectadas por el virus. De este modo, aunque el virus no sea capaz de alcanzar y matar a todas las células tumorales del paciente, el sistema inmune se encargará de eliminar el resto.

Por otro lado, sobre las terapias génicas en general. El pensar en que desde nuestro perfil genético, y desde el fenotipo particular de cada individuo, se puedan desarrollar terapias personalizadas para cada paciente, es increíble, y además, usando virus como vector, como vehículo de genes específicos. Imagino que de momento todo es más generalista, pero entonces, ¿cómo se conjugan los perfiles geno-fenotípicos de un paciente con su tratamiento, y aquí en concreto, para tratar el cáncer?

La terapia génica de enfermedades causadas por la deficiencia de un gen es una realidad. Glybera es virus, en este caso no un adenovirus sino un adenoasociado, en el que sus genes se han sustituido por el gen de la lipoproteína lipasa se usa para curar la deficiencia hereditaria de este gen. Stimvelis es un vector derivado del virus del SIDA, un lentivirus, que se usa para corregir la deficiencia del gen de la adenosina deaminasa que causa una inmunodeficiencia grave.



En cáncer el reto para la terapia génica es mayor pues es necesario corregir o eliminar todas las células tumorales del organismo: una modificación parcial no sería suficiente a no ser que activase una respuesta inmune antitumoral. Los virus oncolíticos se diseñan para crecer en células tumorales con unas características determinadas, como receptores de membrana o alteraciones moleculares determinadas, así que en cierto modo son terapias personalizadas.


Cuando hablamos de terapias personalizadas podemos distinguir terapias apropiadas para un grupo de pacientes que cumplen unas características comunes, es decir, que presentan los marcadores que indican que el virus o el fármaco es eficaz. Ésta sería una terapia a la carta, escogiendo para cada paciente el mejor virus o fármaco entre una “carta” de virus o fármacos. Es algo que ya está ocurriendo en la clínica. En viroterapia, puesto que no se dispone de una “carta” de distintos virus aprobados para uso clínico, todavía no se conjuga un perfil genotípico con un tratamiento. Otra personalización más extrema en fase de estudio consiste en fabricar un fármaco para cada paciente, analizando el tumor y dotando al virus o al fármaco de los elementos adecuados para ese tumor. Esta personalización extrema parece necesaria si queremos usar antígenos para inmunizar o vacunar al paciente frente a su tumor. Cada tumor presenta mutaciones distintas que generan antígenos distintos reconocibles por el sistema inmune del paciente. La vacuna personalizada se puede generar a partir del material del propio tumor, a modo de trasplante autólogo, o bien identificando los antígenos del tumor y sintetizando una vacuna contra ese tumor. El reto de estas terapias futuras totalmente personalizadas es el coste de hacer un fármaco para un paciente y que, puesto que el paciente tiene cáncer, la rapidez con la que se tienen que preparar para cada paciente.

Vuestra reciente publicación “Oncolytic adenoviral delivery of an EGFR-targeting T cell engager improves antitumor efficacy” en Cancer Research es realmente interesante, pues más allá de usar un virus para que sea él de por sí quien lise, elimine, las células tumorales, vais más allá y hacéis que la célula tumoral, infectada por el virus, exprese el anticuerpo BiTE para que sea reconocido y eliminado por nuestros propios linfocitos T. Es una maravilla de diseño. Háblanos por favor cómo fue su estudio, desarrollo, y sobre todo, las posibilidades para las futuras terapias.

El BiTE (de “Bispecific T-cell Engager”) es una proteína sintética formada por la unión de dos fragmentos de anticuerpos que actúa a modo de puente entre la célula tumoral y el linfocito T. Esta unión activa el linfocito para matar la célula tumoral. El diseño y aplicación de BiTEs contra el cáncer impulsado por compañías como Micromet y ahora Amgen, nos inspiró la idea de usar adenovirus oncolíticos productores de BiTEs. Dado que el virus genera una respuesta inmune que atrae a muchos linfocitos al tumor para eliminar células infectadas por el virus, sería ideal redirigir estos linfocitos hacia las células tumorales no infectadas. Aunque hace cinco años cuando empezamos a trabajar en esta idea no teníamos constancia de que otros grupos la hubiesen tenido, como suele ocurrir, un grupo de EEUU trabajando con Vaccinia Virus oncolíticos también ha desarrollado el mismo concepto. Las patentes de BiTEs de Micromet, adquiridas por Amgen, protegen el uso de BiTEs desde cualquier vector, así que el desarrollo hacia ensayos clínicos de estos virus requiere alcanzar acuerdos con esta compañía. El BiTE que hemos publicado reconoce el receptor EGFR de las células tumorales. Más allá de la idea más o menos original de armar un virus con un BiTE, hay que resaltar la dificultad y el valor de los estudios que demuestran el potencial de la misma, cuya responsabilidad en nuestro entorno recae en estudiantes de doctorado, y en este caso en uno excepcionalmente genial, Carlos Alberto Fajardo. Ahora estamos realizando estudios con BiTEs que reconocen células que forman parte del tejido conectivo o estroma del tumor y que impiden la diseminación del virus oncolítico, como los fibroblastos tumorales. Pensamos que complementar la eliminación de células tumorales por el virus oncolítico con la eliminación del estroma tumoral por los linfocitos T puede ser más eficaz que dirigir el virus y los linfocitos hacia la célula tumoral.

Cuando se va profundizando en vuestros trabajos la verdad es que impresiona el nivel, digamos, de complejidad estratégica que hay que elaborar para combatir el cáncer, entonces, ¿qué otros frentes de investigación tenéis abiertos, qué otros diseños de bioingenieria terapéutica, en realidad, para eliminar las células tumorales?
 
Somos un pequeño grupo centrado sobre todo en adenovirus oncolíticos. Tenemos proyectos para mejorar la llegada por vía sanguínea del virus a los tumores, su diseminación intratumoral y la activación de respuestas inmunes antitumorales. Hemos diseñado virus que se unen a la albúmina sérica para esconderse de los anticuerpos que el paciente genera contra el virus. Esto podría permitir aumentar la eficacia de las re-administraciones del virus.



Otra estrategia muy interesante que hace años estamos estudiando en colaboración con los doctores Manuel Ramírez Orellana y Javier García Castro de Madrid, es el uso de células mesenquimales para transportar el virus y activar una respuesta inmune frente al tumor.


Finalmente, dado el auge reciente de la inmunoterapia del cáncer, estamos explorando el uso de adenovirus oncolíticos como vacunas que expresan antígenos tumorales. 

Estaba pensando en que se está avanzando enormemente en la eliminación del cáncer, pero, yendo un poquito más allá, ¿cómo podrían los avances en terapia génica adaptarse para prevenirlo, para hacer que fuera imposible desarrollarlo, pasando de ser terapia génica a prevención génica? ¿Qué tipos de estudios hay o podría haber en esta dirección?

Difícil pregunta. Este concepto de prevención génica está muy poco elaborado. Puesto que hay genes cuya alteración o mutación predispone al cáncer, como genes que reparan los errores que se cometen durante la replicación del ADN celular, la terapia génica para corregir estas alteraciones se consideraría preventiva. Pero se me hace difícil pensar en una terapia génica que haga que una persona nunca pueda desarrollar un cáncer. La génesis de cáncer es multifactorial y está ligada a cambios que se producen en nuestro ADN que se podrían considerar “errores” que se van acumulando con el tiempo. Pero sin estos cambios no habría evolución. La mutación o el cambio es la base de la evolución, detenerla no sé a dónde nos llevaría. En cualquier caso, creo que habrá que esperar avanzar en el desarrollo de la terapia génica terapéutica para abordar la preventiva. Por otra parte, antes de pensar en una modificación genética preventiva sería sensato avanzar en otras maneras más simples de prevenir en cierto grado el cáncer a través de nuestra conducta (vacunación contra el papilomavirus, tabaquismo, sendentarismo, etc.).  

Ya para terminar, sobre las células madre, las células pluripotenciales y la terapia celular, ¿qué principales vías de estudio se están desarrollando, o que encuentras más interesantes, para el tratamiento de enfermedades?

Sin ser un experto en este tema, creo que las células madre supondrán una revolución terapéutica para enfermedades en la que existe una degeneración de tejidos u órganos, como el infarto de miocardio, diabetes, cirrosis, o enfermedades neurodegenerativas como el Alzheimer o Parkinson o para el tratamiento de heridas o traumatismos, como fístulas o traumatismos óseos, articulares o de médula espinal. Se está avanzando en entender qué células será necesario implantar para regenerar los órganos afectados y cómo reprogramar las células madre hacia las mismas. Pensando en el futuro, me parece muy interesante el concepto de la reprogramación in vivo, es decir en el propio organismo.

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Ramón Alemany

Ramón Alemany

Doctor en Biología por la Universidad de Barcelona. Realizó sus estudios de doctorado en el Instituto Municipal de Investigación Médica –IMIM– de Barcelona. En 1993 inició su experiencia postdoctoral en Terapia Génica del cáncer en el MD Anderson Cancer Center de Houston, Texas. Sus investigaciones sobre vectores adenovirales y adenovirus oncolíticos prosiguieron en Chicago como Científico de Baxter Healthcare Corporation y posteriormente, en la Universidad de Alabama en Birmingham. En el año 2001 regresó a España para dirigir el Grupo Viroterapia del Cáncer de investigación del Instituto Catalán de Oncología (ICO)/Instituto de Investigación Biomédica de Bellvitge (IDIBELL), que ahora forma parte del Programa ProCure. Ha publicado más de 110 artículos y 14 patentes en el campo de la utilización terapéutica de adenovirus como vectores de genes o virus oncolíticos. Es editor de las revista “Human Gene Therapy” y “Molecular Therapy-Oncolytics”, consejero de varias compañías biotecnológicas que desarrollan virus terapéuticos y Presidente de la Sociedad Española de Terapia Génica y Celular. En el año 2009 cofundó VCN Biosciences como spin-off de su grupo de investigación.

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