Kedar Hastak, PhD
Sr. Field Applications Scientist
Thursday, October 21, 2021 | 11:10 – 12:10 JST
Oral Presentation: Enabling diagnostic capabilities and composite biomarker discovery for precision cancer therapy with an enhanced exome and transcriptome platform
To enable the identification of composite biomarkers that combine tumor- and immune-related information from both DNA and RNA, we have developed a whole exome/transcriptome-based diagnostic platform called the Personalis NeXT platform. By co-optimizing assay and analytics design, we enable sensitive evaluation of clinically-relevant cancer biomarkers from a single FFPE sample and low quantities of DNA and RNA, while providing a broader evaluation of neoantigens, HLA typing and LOH, antigen processing machinery (APM), TCR/BCR repertoire, immune expression signatures, tumor-infiltrating lymphocytes (TILs), oncoviruses, and germline variants. Validation of the NeXT platform demonstrated high sensitivity and specificity to somatic variants across ~20,000 genes at allelic fractions as low as 5%, with clinical diagnostic reporting on actionable mutations in 247 cancer-driver genes that have been boosted further for higher sensitivity. For neoantigen prediction, we trained our own neural networks using immuno-peptidomic data from monoallelic HLA-transfected to predict pMHC binding. For TCRα/β analysis, we demonstrated excellent reproducibility in top clones and aggregate metrics. We achieved genotyping accuracy of 100% for HLA Class I, and 98.3% for HLA Class II, and have developed and verified the performance of a tool for HLA LOH detection. Further, in a cohort of 51 late-stage melanoma patients, the integration of neoantigen burden, HLA LOH, and APM mutational data formed a neoantigen-based composite biomarker that more accurately predicted response to checkpoint blockade than other markers such as TMB. Thus, this broad diagnostic assay can be leveraged for the development of advanced composite biomarkers; enabling more accurate stratification of patient immunotherapy response.