Abstract
Background Anti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is mostly T cell-mediated. We previously showed that the presence of NY-ESO-1-reactive and/or Melan-A-reactive T cells in the blood correlated with prolonged overall survival (OS) of patients with melanoma with a heterogeneous treatment background. Here, we investigated whether such reactive T cells can also be informative for clinical outcomes in metastatic melanoma under PD-1 immune-checkpoint blockade (ICB). Methods Peripheral blood T cell stimulation by NY-ESO-1 and Melan-A overlapping peptide libraries was assessed before and during ICB in two independent cohorts of a total of 111 patients with stage IV melanoma. In certain cases, tumor-infiltrating lymphocytes could also be assessed for such responses. These were characterized using intracellular cytokine staining for interferon gamma (IFN- 3), tumor negrosis factor (TNF) and CD107a. Digital pathology analysis was performed to quantify NY-ESO-1 and Melan-A expression by tumors. Endpoints were OS and progression-free survival (PFS). Results The initial presence in the circulation of NY-ESO-1- or Melan-A-reactive T cells which became no longer detectable during ICB correlated with validated, prolonged PFS (HR:0.1; p>0.0001) and OS (HR:0.2; p=0.021). An evaluation of melanoma tissue from selected cases suggested a correlation between tumor-resident NY-ESO-1- and Melan-A-reactive T cells and disease control, supporting the notion of a therapy-associated sequestration of cells from the periphery to the tumor predominantly in those patients benefitting from ICB. Conclusions Our findings suggest a PD-1 blockade-dependent infiltration of melanoma-reactive T cells from the periphery into the tumor and imply that this seminally contributes to effective treatment.
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | e003439 |
| Zeitschrift | Journal for ImmunoTherapy of Cancer |
| Jahrgang | 9 |
| Ausgabenummer | 12 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 21.12.2021 |
Fördermittel
Competing interests CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche; and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. BW reports receiving commercial research grants from, is a consultant/ advisory board member for, and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. F. Meier reports receiving commercial research grants from Novartis and Roche; and has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LF reported grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, and Novartis Foundation as well as an advisory role for Novartis, Sanofi, Philogen and Bristol-Myers Squibb. PT has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, consultant’s honoraria from Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi, Kirin Kyowa, and Roche and travel support from Bristol-Myers Squibb and Pierre-Fabre. SF reports receiving speaker’s fees by TAKEDA Pharmaceutical. TE has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Almiral Hermal, and Roche, consultant’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Pierre Fabre and Roche. TS and HN received a research grant from Novartis. GP has received speaker’s honoraria from Novartis, Roche, GlaxoSmithKline and Astellas. MWL is a coinventor of several patents owned by Immatics Biotechnologies, and has acted as a consultant and/or advisory board member for Boehringer Ingelheim Pharma Gmbh & Co. KG. HZ is employed by CeGaT GmbH. KW-H received commercial research grants from the CatalYm GmbH and travel support from SITC (Society for Immunotherapy of Cancer). No potential conflicts of interest were disclosed by the other authors. KW-H is the guarantor for this manuscript. Funding This work was partially funded by Bristol-Myers Squibb (CA209-9P4), Merck Sharp & Dohme (52518), the Klaus Tschira Foundation (00.316.2017), and the Medical Faculty of the University of Tübingen (2509-0-0). Article Processing Charges were partly covered by the Open Access Publishing Fund of the University of Tübingen. 1Department of Dermatology, University Medical Center, Tübingen, Germany 2Institute for Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland 3Department of General, Visceral and Transplant Surgery, University Hospital, Tübingen, Germany 4Skin Cancer Center at the University Cancer Centre and National Center for Tumor Diseases Dresden; Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany 5Department of Dermatology, University of Lübeck, Lübeck, Germany 6German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany 7Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany 8Health Sciences North Research Institute of Canada, Sudbury, Ontario, Canada 9Department of Immunology, University of Tübingen, Tübingen, Germany 10Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany 11Department for Internal Medicine I, University Medical Center, Tübingen, Germany Acknowledgements We thank Silvia Wagner, Shannon Ottmann, Anne Mohrholz, Laura Wenke, Jenny Koop, Archana Yoganandarajah, Ulrich Schweizer, and Jürgen Winter for their support during sample collection and archiving and acknowledge the support by Open Access Publishing Fund of the University of Tübingen.
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