Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage–specific antigen gp100 on HLA-A∗02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator’s choice (n = 126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced, and expression of melanocytic genes decreased, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival as patients without a rash in the phase 3 randomized trial IMCgp100-202 (hazard ratio = 0.84, 95% confidence interval = 0.53–1.32). In summary, skin rash is an off-tumor, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

中文翻译：

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Tebentafusp 在带有黑素细胞的皮肤中诱导 T 细胞驱动的皮疹，这是一种与作用机制一致的不良事件


Tebentafusp 是一种 gp100xCD3 双特异性 ImmTAC，旨在将多克隆 T 细胞重定向到针对 HLA-A*02:01 上呈递黑素细胞谱系特异性抗原 gp100 的细胞。与皮肤相关的不良事件（主要是皮疹）很常见，并且发生在初次输注后几小时内；然而，其机制尚不清楚。在这项研究中，我们分析了 tebentafusp (n = 252) 与研究者选择 (n = 126) 的随机 3 期试验 (NCT03070392) 的临床数据。对 1 期试验 (NCT01211262) 中收集的 19 名患者的配对治疗皮肤样本进行了转化分析。我们的分析表明，皮疹是 tebentafusp 诱导 T 细胞募集到皮肤黑素细胞的临床表现。皮疹的发展取决于皮肤中 gp100 和其他黑色素途径基因的基线表达水平。治疗后，黑素细胞数量减少，黑素细胞基因表达减少，而与免疫和细胞因子信号传导相关的基因表达增加。根据基线预后特征进行调整后，在 tebentafusp 治疗第一周内出现皮疹的患者与 3 期随机试验 IMCgp100-202 中无皮疹的患者具有相同的总生存期（风险比 = 0.84，95% 置信区间 = 0.53–1.32） ）。总之，皮疹是 tebentafusp 针对 gp100+ 黑素细胞的一种非肿瘤、中靶效应，符合其作用机制。