Dramatic responses to high dose ipilimumab plus temozolomide

Published: 26 February 2024| Version 1 | DOI: 10.17632/nmb8csghjc.1
Muhammad Zaki Hidayatullah Fadlullah Wilmot, Julie Williamson, Siwen Hu-Lieskovan, Aik Choon Tan


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.


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Whole exome sequencing of the samples was performed at the Tempus Lab, Inc. (Chicago, IL.) Fastq were aligned to the human reference genome GRCh38 using BWA. Next, PCR duplicates were removed, and somatic variants (INDELs and SNVs) were called using Illumina’s Manta and Strelka2 software. The alignment, variant calling, variant annotations were integrated in containerized Snakemake workflows that are publicly available at https://github.com/HuntsmanCancerInstitute/Workflows.


Huntsman Cancer Institute, University of Utah


RNA Sequencing