Association of Checkpoint Inhibitor-Induced Toxic Effects with Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer

Lukas Flatz, Fiamma Berner, David Bomze, Stefan Diem, Omar Hasan Ali, Mirjam Fässler, Sandra Ring, Rebekka Niederer, Christoph J. Ackermann, Petra Baumgaertner, Natalia Pikor, Cristina Gil Cruz, Willem Van De Veen, Mübeccel Akdis, Sergey Nikolaev, Heinz Läubli, Alfred Zippelius, Fabienne Hartmann, Hung Wei Cheng, Gideon HöngerMike Recher, Jonathan Goldman, Antonio Cozzio, Martin Früh, Jacques Neefjes, Christoph Driessen, Burkhard Ludewig, Ahmed N. Hegazy, Wolfram Jochum, Daniel E. Speiser

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

298 Citations (Scopus)

Résumé

Importance: Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy. Objective: To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer. Design, Setting, and Participants: This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year. Main Outcomes and Measures: Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations). Results: Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P <.001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy. Conclusions and Relevance: These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.

langue originaleAnglais
Pages (de - à)1043-1047
Nombre de pages5
journalJAMA Oncology
Volume5
Numéro de publication7
Les DOIs
étatPublié - 1 juil. 2019
Modification externeOui

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