Staeger Ramon, Tastanova Aizhan, Ghosh Adhideb, Winkelbeiner Nicola, Shukla Prachi, Kolm Isabel, Turko Patrick, Benlahrech Adel, Harper Jane, Broomfield Anna, Camera Antonio, Ambrosio Marianna, Haunerdinger Veronika, Cheng Phil F, Ramelyte Egle, Pham James, Kreutmair Stefanie, Becher Burkhard, Levesque Mitchell P, Dummer Reinhard, Meier-Schiesser Barbara
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Medical Faculty, University of Zurich, Zurich, Switzerland.
J Clin Invest. 2025 Apr 29;135(12). doi: 10.1172/JCI181464. eCollection 2025 Jun 16.
BACKGROUNDTebentafusp 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.METHODSThis study investigated immunological and cellular responses using single-cell and spatial analysis of skin biopsies from patients with metastatic uveal melanoma treated with tebentafusp.RESULTS81.8% 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 colocalized 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.CONCLUSIONSequential 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.FUNDINGCancer Research Foundation, Swiss National Science Foundation (323630_207029, 733 310030_170320, 310030_188450, CRSII5_183478), Iten-Kohaut Foundation, European Research Council no. 882424, University Priority Project Translational Cancer Research of the University of Zurich (UZH), UZH PostDoc grant (K-85810-02-01).
背景
替贝福司是首个获批用于临床治疗HLA-A*02:01+不可切除/转移性葡萄膜黑色素瘤成年患者的基于T细胞受体的双特异性蛋白。它将T细胞重定向至表达gp100的靶细胞，常引发与皮肤相关的早期不良事件。
方法
本研究通过对接受替贝福司治疗的转移性葡萄膜黑色素瘤患者的皮肤活检进行单细胞和空间分析，来研究免疫和细胞反应。
结果
81.8%的患者出现急性皮肤不良事件，这与生存期改善相关。多模态分析显示CD4+和CD8+ T细胞大量浸润，而黑素细胞数量减少。单细胞RNA测序显示T细胞活化、增殖以及IFN-γ/细胞毒性基因上调。CD8+ T细胞与黑素细胞共定位且LAG3上调，提示与替贝福司联合治疗的潜力。黑素细胞上调抗原呈递和凋亡途径，而色素沉着基因表达下降。然而，gp100仍稳定表达。
结论
连续的皮肤活检能够对替贝福司进行体内药效学建模，为免疫激活、毒性和治疗反应提供见解。在适合纵向采样的组织中检查双特异性药物的靶向效应，可增强我们对毒性和治疗逃逸机制的理解，为治疗优化策略提供指导。
资助
癌症研究基金会、瑞士国家科学基金会（323630_207029、733 310030_170320、310030_188450、CRSII5_183478）、伊滕-科豪特基金会、欧洲研究理事会第882424号、苏黎世大学（UZH）大学优先项目转化癌症研究、UZH博士后资助（K-85810-02-01）。
