Biorthogonal Catalytic Scaffold for in situ Personalized Cancer Chemo-Immunotherapy

Descripción del proyecto

Hidrogeles especializados para el tratamiento combinado contra el cáncer

Las inmunoterapias contra el cáncer han transformado el tratamiento, pero muchos pacientes experimentan una respuesta limitada o graves efectos secundarios, lo que pone de relieve la necesidad de nuevas estrategias. El equipo del proyecto BiorthoCat-Immuno, que cuenta con el apoyo de las Acciones Marie Skłodowska-Curie, desarrollará un hidrogel catalítico implantable para mejorar la quimioinmunoterapia mediante química biortogonal, que permite activar fármacos sin interferir en los procesos biológicos naturales. El hidrogel liberará localmente dos fármacos: un quimioterapéutico para destruir las células cancerosas y un inmunoestimulante para desencadenar una respuesta inmunitaria. Combinando el diseño de materiales con la química catalítica, el implante promoverá la muerte celular específica del tumor, la liberación de antígenos y la activación de células inmunitarias, con lo que se creará una vacuna personalizada contra el cáncer. Se trata de un método innovador, localizado y destinado a mejorar tanto la seguridad como la eficacia del tratamiento contra el cáncer.

Objetivo

In this fellowship I will leverage the recent advances in biorthogonal chemistry to develop an implantable catalytic hydrogel for chemoimmunotherapy through transition metal-mediated biorthogonal drug uncaging. The past decade saw incredible advances in the field of cancer immunotherapies, with immune checkpoint blockade therapies and chimeric antigen receptor-T cell therapies demonstrating clinical efficacy. However, issues still exist, as life-threatening side effects and limited patient response. Therefore, there is a huge need for innovative solutions to improve immunotherapies outcome. This project seeks to apply the materials and reaction engineering competence of the applicant, together with the biomaterials expertise of the Stevens lab (Karolinska Institute) to design a nanocatalyst-doped hydrogel with tailored geometry, as the first biorthogonal catalytic system for cancer immunotherapy. The biomaterial developed in this fellowship will address cancer immunotherapy through a completely unexplored approach: catalytic uncaging of non-toxic prodrugs to their active form through metal-catalyzed depropargylation reactions, completely orthogonal to biological processes. The implant will enable uncaging of two toxic drugs: a chemotherapeutic – doxorubicin – inducing immunogenic cell death, and an immunostimulant drug – R848, a TLR7/8 agonist. The combination of drugs activated by the implant will enable localized cancer cells death with release of cancer-specific antigens, antigens then uptaken by antigen presenting cells, eventually eliciting antitumor immunity, towards a personalized cancer vaccine. The design of the scaffold will be guided by principles of biomaterials design and catalytic reaction engineering. Working in the Stevens lab I will access state-of-the-art equipment for materials synthesis and characterization, and cutting edge facilities to study the cell-material interactions in vitro and characterize the efficacy of the envisioned treatment.