2026-10-15T22:41:06Z https://data.mendeley.com/oai

oai:data.mendeley.com/nmb8csghjc.1 2024-02-26T12:40:12Z

Fadlullah Wilmot, Muhammad Zaki Hidayatullah Dramatic responses to high dose ipilimumab plus temozolomide Mendeley Data Background: Despite advancements in checkpoint inhibitor-based immunotherapy, patients with advanced melanoma who have progressed on standard dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Several studies support a dose-response activity of Ipi, and one promising combination is Ipi 10mg/kg (Ipi10) + temozolomide (TMZ). Methods: We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10+TMZ in the immunotherapy refractory/resistant setting (n = 6), using similar patients treated with Ipi3+TMZ (n = 6) as comparison. Molecular profiling by whole exome sequencing (WES) and RNA-seq of tumors harvested through one responder’s treatment was performed. Results: With a median follow up of 119 days, patients treated with Ipi10+TMZ had statistically significant longer median progression free survival of 144.5 days (range 27–219) vs 44 (26–75) in Ipi3+TMZ, p=0.04, and a trend for longer median overall survival of 154.5 days (27–537) vs 89.5 (26–548). All patients in the Ipi10 cohort had progressed on prior Ipi+Nivo. WES revealed only 12 shared somatic mutations including BRAF V600E. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastatic lesions after standard dose Ipi + nivo and Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators including Wnt and TGFb signaling. Conclusion: Ipi10+TMZ demonstrated efficacy including dramatic responses in patients with advanced melanoma refractory to prior Ipi + anti-PD1, even with CNS metastases. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher dose Ipi is required for some patients. RNA Sequencing Williamson, Julie Hu-Lieskovan, Siwen Tan, Aik Choon Dataset doi:10.17632/nmb8csghjc.1 oai:data.mendeley.com/nmb8csghjc.1 Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 https://data.mendeley.com/datasets/nmb8csghjc 2024-02-26T12:40:12Z