Enhancing TCR-T cell therapy by combinatorial therapeutic approaches to target neoantigen-positive cancers

Descripción del proyecto

Estrategias combinatorias para optimizar la inmunoterapia con receptores de linfocitos T dirigida a neoantígenos

Los carcinomas broncopulmonares no microcíticos representan el 80 % de todos los casos de cáncer de pulmón. A pesar de ciertos avances con los tratamientos basados en puntos de control inmunitario, muchos pacientes no responden o desarrollan resistencia, lo que destaca la necesidad desarrollar estrategias más eficaces. Para abordar este problema, el proyecto NeoCure, financiado por el Consejo Europeo de Investigación, empleará la ingeniería de receptores de linfocitos T (RLT) para actuar de forma selectiva sobre neoantígenos tumorales. Ya se han identificado dos neoantígenos prevalentes a partir de mutaciones promotoras de KRAS (G12V y G12C) y se han aislado sus RLT cognados. Además, el equipo del proyecto ha demostrado un tratamiento innovador que combina quimioterapia linfodepletiva con inmunoterapia basada en RLT específicos para KRAS G12V, con el fin de mejorar la presentación de neoantígenos y la destrucción tumoral. Ahora, el objetivo de NeoCure es evaluar otras terapias combinatorias mediante el acoplamiento de sus linfocitos T-RLT específicas para KRAS con estrategias quimioterapéuticas mejoradas y vacunas de ARN mensajero dirigidas a neoantígenos.

Objetivo

"Non-small-cell-lung-cancer (NSCLC) remains one of the most lethal cancers (≈1.5 million deaths annually), and current treatments fail to achieve universal, lasting remissions. While immune checkpoint therapies have improved NSCLC outcomes, many patients either do not respond or relapse, underscoring an urgent need for new, more effective strategies. NeoCure directly addresses this need by harnessing T-cell receptor (TCR) engineering to target tumor-specific neoantigens. In our prior research (ERC#101094980), we identified two prevalent neoantigens from common KRAS driver mutations (G12V and G12C) and isolated their cognate TCRs, which specifically recognize and eliminate cancer cells bearing these mutations. Notably, these KRAS G12V/C mutations (in the context of HLA-A*03:01) occur in an estimated 120,000 new lung, colon, and pancreatic cancer cases each year, highlighting the broad impact and commercial potential of this targeted approach.
We have demonstrated a breakthrough combinatorial therapy: adding a lymphodepleting chemotherapy to KRAS G12V-specific TCR-T cell therapy significantly enhances neoantigen presentation and tumor killing. Building on this finding, NeoCure will evaluate novel combination treatments – pairing our KRAS-specific TCR-T cells with optimized chemotherapy regimens and neoantigen-targeted mRNA vaccines – in advanced humanized mouse models. This PoC is designed as a critical step toward clinical translation, aiming for complete tumor elimination in preclinical models. In parallel, we are executing key pre-commercialization activities to ensure a clear path to clinical application. These include engaging with regulatory authorities (FDA/EMA) to align with fast-track approval pathways, forging industry partnerships for co-development, and strengthening our intellectual property around the NeoCure TCRs and therapy platform. Through this comprehensive approach, NeoCure is positioned as a transformative innovation in cancer immunotherapy.
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