Williamson Julie, Fadlullah Muhammad Zaki Hidayatullah, Kovacsovics-Bankowski Magdalena, Gibson Berit, Swami Umang, Erickson-Wayman Alyssa, Jamison Debra, Sageser Dan, Jeter Joanne, Bowles Tawnya L, Cannon Donald M, Haaland Ben, Schroeder Joyce D, Nix David A, Atkinson Aaron, Hyngstrom John, McPherson Jordan, Tan Aik-Choon, Hu-Lieskovan Siwen
Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84112, USA.
Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
Curr Oncol. 2025 Feb 28;32(3):144. doi: 10.3390/curroncol32030144.
Patients with advanced melanoma who progress on standard-dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Studies support a dose-response activity of Ipi, and one promising combination is Ipi 10 mg/kg (Ipi10) + temozolomide (TMZ). We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10 + TMZ in the immunotherapy refractory/resistant setting (n = 6, all progressed after prior Ipi + nivolumab), using similar patients treated with Ipi3 + TMZ (n = 6) as comparison. Molecular profiling by whole-exome sequencing (WES) and RNA-sequencing (RNA-seq) of tumors harvested through one responder's treatment was performed. With a median follow up of 119 days, patients treated with Ipi10 + TMZ had a statistically significant longer median progression-free survival of 144.5 days (range 27-219) vs. 44 (26-75) in Ipi 3 mg/kg (Ipi3) + TMZ, = 0.04, and a trend of longer median overall survival of 154.5 days (27-537) vs. 89.5 (26-548). Two patients in the Ipi10 + TMZ cohort had a partial response, and both responders had BRAF V600E mutant melanoma. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastases after Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators. Ipi10 + TMZ demonstrated efficacy, including dramatic responses in patients refractory to prior Ipi + anti-PD1. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher doses are required for some patients.
在标准剂量的伊匹单抗（Ipi）+纳武单抗治疗中病情进展的晚期黑色素瘤患者预后仍然很差。研究支持伊匹单抗的剂量反应活性，一种有前景的联合方案是伊匹单抗10mg/kg（Ipi10）+替莫唑胺（TMZ）。我们对在免疫治疗难治/抵抗情况下接受Ipi10+TMZ治疗的晚期黑色素瘤患者进行了一项回顾性队列分析（n = 6，所有患者在先前接受Ipi+纳武单抗治疗后病情进展），并将其与接受Ipi3+TMZ治疗的类似患者（n = 6）进行比较。对通过一名缓解者的治疗采集的肿瘤进行了全外显子组测序（WES）和RNA测序（RNA-seq）的分子谱分析。中位随访119天，接受Ipi10+TMZ治疗的患者的中位无进展生存期在统计学上显著更长，为144.5天（范围27 - 219天），而接受3mg/kg伊匹单抗（Ipi3）+TMZ治疗的患者为44天（26 - 75天），P = 0.04，且总生存期有延长趋势，分别为154.5天（27 - 537天）和89.5天（26 - 548天）。Ipi10+TMZ队列中有两名患者出现部分缓解，且两名缓解者均为BRAF V600E突变型黑色素瘤。RNA-seq显示炎症特征富集，包括与原发肿瘤相比，Ipi10+TMZ治疗后转移灶中的干扰素反应，以及负性免疫调节因子下调。Ipi10+TMZ显示出疗效，包括对先前Ipi+抗PD1难治的患者有显著反应。分子数据表明激活足够的抗肿瘤免疫反应可能存在伊匹单抗剂量阈值，部分患者需要更高剂量。
