Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer

Immune checkpoint blockade has significantly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC) and other solid tumours, but many patients do not respond and acquired resistance is common. Aspects of the tumour microenvironment linked to clinical outcomes include the proportion of tumour-infiltrating lymphocytes (TIL), tumour programmed death ligand 1 ( PD-L1) score and tumour mutation burden. Adoptive cell therapy (ACT), a technique that works by infusing ex vivo expanded T lymphocytes to increase the effector cell pool in tumours, is anticipated to become a viable therapeutic option for patients with solid tumours, akin to chimeric antigen receptor T cell (CAR-T) therapy in haematological malignancies. TIL therapy has shown durable clinical responses in heavily pre-treated patients with melanoma and other solid tumours. We review the experience of ACT with TILs and the recent evidence that clonal neoantigens might be the most relevant immunotherapeutic targets in heterogeneous solid tumours such as NSCLC. Clonal (or truncal) neoantigens arise from the earliest mutagenic events in tumour evolution, and are retained over time in all tumour cells within a patient, making them the ideal target for T cell therapy. NSCLC has one of the highest clonal mutation burdens of all cancers through exposure to carcinogens in tobacco smoke, providing a strong rationale to develop clonal neoantigen reactive T cells (cNeT) for this indication. The first treatment modality to test this concept clinically is ATL001, a cNeT product that is derived from autologous TILs and enriched for T cells specifically recognizing clonal neoantigenic epitopes by selective expansion. Clinical studies of ATL001 will commence in 2019.