Melanoma Clonal Heterogeneity Leads to Secondary Resistance after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes
David König, Michael T. Sandholzer, Sarp Uzun, Andreas Zingg, Reto Ritschard, Helen Thut, Katharina Glatz, Elisabeth A. Kappos, Dirk J. Schaefer, Christoph Kettelhack, Jakob Passweg, Andreas Holbro, Katharina Baur, Michael Medinger, Andreas Buser, Didier Lardinois, Lukas T. Jeker, Nina Khanna, Frank Stenner, Benjamin Kasenda, Krisztián Homicskó, Matthias S. Matter, Natália Rodrigues Mantuano, Alfred Zippelius, Heinz Läubli
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.