ALK-driven cancers: a Portfolio of ONcoimmunoTherapies to achieve tumor Eradication

Descripción del proyecto

Apuntar a células cancerosas residuales de linfoma anaplásico de quinasa positivas

El gen de linfoma anaplásico de quinasa (ALK, por sus siglas en inglés) produce una proteína receptora que es importante para el desarrollo del sistema nervioso y que puede expresarse de forma anormal en determinados tipos de cáncer. Cuando muta o se fusiona, el gen ALK impulsa el crecimiento celular descontrolado, causando algunos cánceres de pulmón, linfomas, neuroblastomas y otras neoplasias malignas. Los inhibidores de la tirosina quinasa ALK (TKI, por sus siglas en inglés) pueden reducir inicialmente el tamaño de los tumores y mantener una enfermedad residual mínima (ERM), pero las recaídas son frecuentes y el pronóstico es malo. El proyecto A-PONTE, financiado por el Consejo Europeo de Investigación, tiene como objetivo eliminar las células ALK positivas residuales antes de la recaída mediante inmunoterapias con linfocitos T dirigidas contra ALK. Las células CAR-T se dirigen al ALK de la superficie tumoral, mientras que las células TCR-T reconocen los péptidos generados por el ALK intracelular. En combinación con vacunas u otros métodos, pueden eliminar la MRD durante la remisión, lo que ofrece posibles curas.

Objetivo

Cancers driven by the oncogenic activation of the ALK gene include subsets of non-small cell lung cancer, lymphoma, neuroblastoma, melanoma, glioblastoma, thyroid cancer, stromal tumors and other hematologic malignancies and solid tumors. Typically, these cancers affect children or young adults in healthy conditions with a long expectancy of life. They are currently treated with ALK tyrosine kinase inhibitors (TKIs) either in first line or at relapse after other standard therapies. ALK TKIs reduce tumor burden dramatically, and often induce a prolonged state of minimal residual disease (MRD) resulting in several years of extended survival. Eventually, most ALK+ tumors become resistant to ALK TKIs by different mechanisms. Relapses occur in >90% of patients that are then left without efficacious therapies and face a dismal prognosis. This common pattern of evolution of ALK+ tumors, characterized by a prolonged state MRD before the fatal relapse, provides a window of opportunity to develop therapies that might be curative should ALK+ persister cells be fully eradicated.
In this proposal, we will develop, test and validate a portfolio of ALK-directed T cell immunotherapies to achieve eradication of residual ALK+ cells during the MRD state induced by ALK TKIs. These immunotherapies include potentiated ALK.CAR-T cells for tumors that express ALK on the surface, and ALK.TCR-T cells for tumors that express ALK internally in the cytoplasm. ALK-directed T cell immunotherapies will be tested alone or in novel modalities of combination between them, with ALK vaccines or with other approaches to further potentiate their anti-tumoral efficacy. We will empower these ALK immunotherapies to eradicate MRD based on the ALK genetic alteration that is specific to each tumor. We envision that the combination of ALK TKIs with ALK-directed T cell immunotherapies could achieve a complete cure in a large subset of patients with ALK+ tumors before the onset of relapse or metastatic spread.