33 Dynamic monitoring of response to immune checkpoint blockade through deep-learning empowered ultra-sensitive liquid biopsy in melanoma. (9th November 2020)

• Record Type: Journal Article
• Authors: Widman, Adam; Khamnei, Cole; Bass, Jake; Liao, Will; Shah, Minita; Robine, Nicolas; Wolchok, Jedd; Callahan, Margaret; Landau, Dan
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A32
• Page End: A34
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0033
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Clearance of circulating tumor DNA (ctDNA) following checkpoint blockade (CB) can precede radiographic response, 1 2 though current state of the art ctDNA detection via targeted panels faces limited sensitivity in low burden disease (figure 1). We previously showed that whole genome sequencing (WGS) of plasma can overcome low input of ctDNA to dynamically track low volume malignancy using matched tumor tissue. 3 We therefore sought to evaluate ctDNA for tracking early response to checkpoint blockade (CB) in melanoma, and developed a novel classifier that allows us to track disease without matched tumor tissue for expanded applicability in immunotherapy. Methods: To identify ctDNA sparsely diluted in noncancerous plasma cell free DNA (cfDNA), we developed Phoenix, a deep-learning classifier that uses genomic and epigenomic features to distinguish single nucleotide variants (SNVs) in melanoma from sequencing noise. We evaluated Phoenix on a retrospective cohort of serially sampled plasma from patients with advanced cutaneous melanoma on CB (nivolumab alone or with ipilimumab). Plasma was collected at 0, 3, 6 and 12 weeks after first dose of immunotherapy. ctDNA dynamics were compared to radiographic imaging results at 12 weeks. Results: We trained Phoenix on tumor-confirmed SNVs in plasma from a single patient with high tumor mutational burden (TMB) melanoma and cfDNA from age-matched patients without known cancer. Overall ctDNA signal-to-noise enrichment ranged from 100 - 260x in validation patients (n=2) with bulky disease. Phoenix learned key features of melanoma ctDNA including the UV mutational signature and short fragment size (figure 2), and sensitively tracked persistent low burden disease seen on imaging (figure 3). To validate these findings, we expanded our cohort (n= 15) of serially tracked tumors. In our preliminary analysis of 12 patients, Phoenix detected pretreatment ctDNA in 92% of patients at a specificity of 97% (figure 4), compared with only 17% with the benchmark in the field (iChorCNA, a plasma-based WGS liquid biopsy tool; table 1). Phoenix detected a decrease in ctDNA 3 weeks after initiation of CB in 80% of patients (figure 5) with an objective response on imaging. No change in ctDNA was seen in patients who did not respond to treatment. Conclusions: Phoenix successfully identified pretreatment melanoma ctDNA without matched tumor tissue and identified response to CB as early as 3 weeks after treatment. Our ongoing studies aim to optimize this technology for early identification of CB response in clinical practice. Acknowledgements: Thanks to support from the Conquer Cancer Foundation Ethics Approval: Use of human data in this study was approved by Memorial Sloan Kettering's IRB, Assurance Number FWA0000499 References: Zhang Q, Luo J, et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Discov 2020 pp: CD-20-0047. doi:10.1158/2159-8290.CD-20-0047 Bratman SV, Yang SYC., Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer (2020). https://doi.org/10.1038/s43018-020-0096-53. Zviran A, Schulman RC, Shah M, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med 2020;26(7):1114–1124. doi:10.1038/s41591-020-0915-3 Adalsteinsson VA, Ha G, Freeman SS, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun 2017;8(1):1324. Published 2017 Nov 6. doi:10.1038/s41467-017-00965-y