Melanoma clonal heterogeneity leads to secondary resistance after adoptive cell therapy with tumor-infiltrating lymphocytes

Abstract Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT. Synopsis: Mechanisms of resistance to TIL-ACT are ill-defined. The authors report that transfer of TILs caused immune selection of a resistant melanoma cell clone in one patient. T-cell collection from multiple tumor sites could help overcome this issue.