Development of an immune-armed therapeutic adenoviral platform for pediatric brain tumors

Descripción del proyecto

Terapia vírica oncolítica para tumores encefálicos infantiles malignos

Los virus oncolíticos se diseñan para infectar y destruir de forma selectiva células cancerosas y, al mismo tiempo, favorecer una respuesta inmunitaria antitumoral. Se han posicionado como un tratamiento antineoplásico muy prometedor. El proyecto POPCORN, financiado por el Consejo Europeo de Investigación, tiene como objetivo desarrollar una terapia vírica oncolítica de nueva generación para el glioma difuso de la línea media, uno de los tumores encefálicos infantiles de mayor malignidad, con una supervivencia media inferior a catorce meses. Sus investigadores se proponen genomodificar adenovirus oncolíticos para que administren anticuerpos inmunomoduladores de dominio único directamente al tumor. Al aumentar la función inmunoestimuladora de los virus oncolíticos, el estudio podría proporcionar un tratamiento revolucionario para los tumores encefálicos infantiles más difíciles.

Objetivo

Diffuse Midline Gliomas (DMGs) are the most aggressive pediatric brain tumors in desperate need of curative treatment. The median life expectancy of these children remains below 14 months after diagnosis, and nearly none survive beyond the second year. Similarly, for other high-risk pediatric brain tumors, there is hardly any option after recurrence, and long-term survivors are faced with life-long sequelae that impact their quality of life. In this scenario, there is an urgent need for innovative, efficacious, and safe therapies for these patients. Oncolytic viruses are promising anticancer biotherapeutic agents that offer a unique combination of safety profile, direct antineoplastic activity, and the induction of anti-tumor immune responses. Recently, a Phase I clinical trial showed that combining the oncolytic adenovirus Delta-24-RGD and radiotherapy is non-toxic and results in anti-tumor responses and prolonged median overall survival (17.8 months) in patients. However, results are still insufficient to be curative due to counteracting mechanisms intrinsic to the tumor microenvironment and also triggered by the virus that eventually exceeds its immunostimulatory properties. The proposed technology, termed “POPCORN”', is an oncolytic-based platform capable of expressing immunomodulatory single-domain antibodies directed to intrinsic targets in these tumors. We will develop the POPCORN Proof of Concept using a state-of-the-art experimental approach and validate its safety and efficacy in vitro and relevant in vivo DMG models. We will also perform IND-enabling studies and apply for PUMA/PRIME designation. Additionally, we will work on the IPR strategy, and a value proposition to develop and commercialize the POPCORN platform will be generated. We envision the POPCORN platform becoming a game changer in treating DMGs, providing a one-of-a-kind tool for eliminating these aggressive tumors that could be extensive to other difficult-to-treat pediatric brain tumors.