Live biotherapeutics to potentiate cancer immunotherapy

Descripción del proyecto

Unas bacterias genomodificadas facilitan la administración farmacológica en tumores

Muchos enfoques inmunoterapéuticos son prometedores en un principio, pero están asociados con efectos adversos relacionados con el sistema inmunitario. Se cree que un microambiente tumoral inmunosupresor y hostil impide que la inmunoterapia tenga éxito, ye que limita el suministro de oxígeno y la administración de los fármacos. El equipo del proyecto LiveBioThx, financiado por el Consejo Europeo de Investigación, se propone crear bacterias genomodificadas para que actúen como un vehículo de administración de enzimas al microambiente tumoral. Su idea es reducir la rigidez tumoral y mejorar la perfusión a través de la remodelación del tumor. Se espera que el producto bioterapéutico vivo LiveBioThx mejore la potencia y el resultado clínico de inmunoterapias como los inhibidores de puntos de control.

Objetivo

Immunotherapy, including immune checkpoint inhibitors (ICIs), has revolutionized the treatment of multiple cancers. Anti-tumor responses are often durable but overall only a subset of patients receiving ICIs has exhibited sustained tumor shrinkage, whereas a substantial fraction receiving these therapies develops immune-related adverse events. The absence of dramatic responses is attributed to several factors, including abnormalities in the tumor microenvironment (TME). Specifically, many tumors such as subsets of colorectal, breast and pancreatic cancer, become stiff as they grow. Tumor stiffening causes compression of intratumor blood vessels, impairing blood flow/perfusion and oxygen supply. Hypoperfusion reduces ICIs delivery to the tumor and hypoxia induces immunosuppression, compromising immunotherapy. To restore these abnormalities, a novel therapeutic strategy to normalize tumor stiffness prior to ICIs has been tested in preclinical studies and in the clinic. This strategy repurposes clinically approved drugs to target the factors contributing to tumor stiffening, leading to a new class of therapeutics, known as mechanotherapeutics. However, drug-repurposing poses certain limitations as adding a new drug to the treatment regimen of patients with cancer is not feasible in many cases. As an alternative to these approaches, we propose here to test the ability of engineered live biotherapeutics in the form of programmable bacteria that offer unique advantages for delivering enzymes to normalize the TME. Even a small fraction of bacterial dose reaching the tumor is sufficient to colonize it and allow therapeutic concentrations of tumor-remodeling enzymes to be maintained for a long period of time. We propose to evaluate the ability of a novel live biotherapeutic product to improve perfusion and potentiate ICIs in preclinical tumor models of colorectal and breast tumors. This bacterial product has great potential for commercialization, and a plan is proposed.