Comprehensive Longitudinal ctDNA Monitoring in Metastatic Cancer Patients Treated with an Individualized Neoantigen-directed Vaccine

Schenk, D.; Davis, M. J.; Zhou, R.; Mantilla, A.; Galbraith, M.; Spiro, O.; Petrillo, O.; Faria do Valle, I.; Ferguson, A. R.; Jooss, K.; Dhanik, A.

doi:10.1101/2024.12.04.626817

bioRxiv · 10.1101/2024.12.04.626817

Comprehensive Longitudinal ctDNA Monitoring in Metastatic Cancer Patients Treated with an Individualized Neoantigen-directed Vaccine

Schenk, D.·Davis, M. J.·Zhou, R.·Mantilla, A.·Galbraith, M.·Spiro, O.·Petrillo, O.·Faria do Valle, I.·Ferguson, A. R.·Jooss, K.·Dhanik, A.

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Abstract

PurposeCirculating-tumor DNA (ctDNA) is an emerging, minimally invasive diagnostic and prognostic biomarker for patients receiving a variety of cancer therapies. Comprehensive and robust longitudinal monitoring of ctDNA can provide an understanding of tumor burden, heterogeneity, and response or resistance to treatment. Experimental DesignctDNA of 28 metastatic cancer patients receiving an individualized neoantigen-directed immunotherapy was monitored longitudinally, up to two years, using a unique hybrid next generation sequencing assay targeting tumor-informed and tumor-naive variants. Patient-specific panels were designed targeting an average of 144 variants per patient. A tumor-naive universal panel was also designed for inclusion with patient-specific panels to monitor recurrently mutated tumor hotspots (e.g., KRAS and TP53) and genes implicated in immunotherapy resistance (B2M, TAP1/2). ResultsAnalytical characterization of the assay established linearity with a mean variant allele frequency (VAF) [≥]0.049%, and a variant-level limit of detection (LOD95) of 0.12%. Tumor-informed variants were detected in 26/28 patients, and de novo variants were observed in 25/28 patients. HLA LOH was also observed. Longitudinal ctDNA data provided key insights into patients responses to vaccine treatment. ConclusionsThe hybrid design of the ctDNA monitoring assay provides the sensitivity and specificity required for evaluating patient samples undergoing individualized therapy. It provides an improved capability to understand patient response to experimental therapies and further supports the utility of ctDNA as a cancer biomarker.

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Schenk, D., Davis, M. J., Zhou, R., Mantilla, A., Galbraith, M., Spiro, O., Petrillo, O., Faria do Valle, I., Ferguson, A. R., Jooss, K., Dhanik, A.. 2024-12-07. Comprehensive Longitudinal ctDNA Monitoring in Metastatic Cancer Patients Treated with an Individualized Neoantigen-directed Vaccine. https://doi.org/10.1101/2024.12.04.626817

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