Heinz Läubli

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in melanoma patients, although long-term responses seem restricted to patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. Here, we describe a case of secondary resistance to TIL-ACT likely due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To our knowledge, this is the first case of clonal selection of a pre-existing non-dominant tumor cell clone and it demonstrates a mechanism involved in secondary resistance to TIL-ACT that could potentially change current clinical practice, because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before the treatment with TIL-ACT.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, resistance to ICB occurs frequently due to tumor-intrinsic alterations or extrinsic factors in the tumor microenvironment. This Viewpoint aims to give an update on recent developments in immunotherapy for solid tumors and highlights progress in translational research and clinical practice.