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Clinical Research and Public HealthIn-Press PreviewDermatologyOncology Open Access | 10.1172/JCI181464

Tebentafusp elicits on-target cutaneous immune responses driven by cytotoxic T-cells in uveal melanoma patients

Ramon Staeger,1 Aizhan Tastanova,1 Adhideb Ghosh,2 Nicola Winkelbeiner,1 Prachi Shukla,1 Isabel Kolm,1 Patrick Turko,1 Adel Benlahrech,4 Jane Harper,4 Anna Broomfield,4 Antonio Camera,4 Marianna Ambrosio,1 Veronika Haunerdinger,1 Phil F. Cheng,1 Egle Ramelyte,1 James P. Pham,5 Stefanie Kreutmair,6 Burkhard Becher,6 Mitchell P. Levesque,1 Reinhard Dummer,1 and Barbara Meier-Schiesser1

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Staeger, R. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Tastanova, A. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Ghosh, A. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Winkelbeiner, N. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Shukla, P. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Kolm, I. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Turko, P. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Benlahrech, A. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Harper, J. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Broomfield, A. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Camera, A. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Ambrosio, M. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Haunerdinger, V. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Cheng, P. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Ramelyte, E. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Pham, J. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Kreutmair, S. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Becher, B. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Levesque, M. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Dummer, R. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

2Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

3Department of Dermatology, University Hospital Zurich, Zürich, Switzerland

4Immunocore Ltd, Abingdon-on-Thames, United Kingdom

5Department of Medical Oncology, St Vincent’s Hospital Sydney, Sydney, Australia

6Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Find articles by Meier-Schiesser, B. in: JCI | PubMed | Google Scholar

Published May 1, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI181464.
Copyright © 2025, Staeger et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 1, 2025 - Version history
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Abstract

Background: Tebentafusp is the first T-cell receptor-based bispecific protein approved for clinical use in HLA-A*02:01+ adult patients with unresectable/metastatic uveal melanoma. It redirects T-cells toward gp100-expressing target cells, frequently inducing skin-related early adverse events. Methods: This study investigated immunological and cellular responses using single-cell and spatial analysis of skin biopsies from patients with metastatic uveal melanoma treated with tebentafusp. Results: 81.8% of patients developed acute cutaneous adverse events, which correlated with improved survival. Multimodal analysis revealed a brisk infiltration of CD4+ and CD8+ T-cells, while melanocyte numbers declined. Single-cell RNA-sequencing revealed T-cell activation, proliferation, and IFN-γ/cytotoxic gene upregulation. CD8+ T-cells co-localized with melanocytes and upregulated LAG3, suggesting potential for combination therapies with tebentafusp. Melanocytes upregulated antigen presentation and apoptotic pathways, while pigmentation gene expression decreased. However, gp100 remained stably expressed. Conclusion: Sequential skin biopsies enable in vivo pharmacodynamic modeling of tebentafusp, offering insights into immune activation, toxicity, and treatment response. Examining the on-target effects of bispecifics in tissues amenable to longitudinal sampling enhances our understanding of toxicity and therapeutic escape mechanisms, guiding strategies for treatment optimization.

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  • Version 1 (May 1, 2025): In-Press Preview
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