Chimeric antigen receptor-T cell therapy in solid tumours: breakthroughs, challenges, and future directions

Abstract

This thesis presents chimeric antigen receptor (CAR-T) cell therapy as it is being extended from haematological malignancies into solid tumours, a setting where its success has so far been far more limited. It begins by outlining the biological architecture and mechanism of action of CAR-T cells, including the distinct roles of CD8+ and CD4+ subsets and the five generations of receptor design. The work then reviews current clinical progress against four major solid-tumour targets, HER2, GD2, mesothelin, and EGFR/EGFRvIII, highlighting GD2-directed therapy in neuroblastoma and diffuse midline glioma as the strongest results achieved to date. It goes on to analyse the main barriers limiting efficacy in solid tumours, namely antigen heterogeneity, the immunosuppressive tumour microenvironment, limited T-cell persistence and exhaustion, and treatment-related toxicity. The final chapters explore emerging engineering strategies intended to overcome these barriers, such as logic-gated receptors, protease-activated masking, and T-cell receptor engineering. Overall, the thesis concludes that durable efficacy in solid tumours will depend on simultaneously engineering for antigen specificity, resistance to the microenvironment, cell persistence, and safety, rather than optimising any one of these factors alone.