A5060460344- Immunotherapy and Immune Responses
- vaccines and immunoinformatics approaches
- Monoclonal and Polyclonal Antibodies Research
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Ferroptosis and cancer prognosis
- Lymphoma Diagnosis and Treatment
- Advanced Biosensing Techniques and Applications
- T-cell and B-cell Immunology
- Sarcoma Diagnosis and Treatment
- Gastrointestinal Tumor Research and Treatment
- Molecular Biology Techniques and Applications
- Genetic factors in colorectal cancer
- CAR-T cell therapy research
- Hepatocellular Carcinoma Treatment and Prognosis
- Viral-associated cancers and disorders
- Platelet Disorders and Treatments
- Chemokine receptors and signaling
- Peptidase Inhibition and Analysis
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Pancreatic and Hepatic Oncology Research
- interferon and immune responses
- Medical Imaging and Pathology Studies
- Immune Cell Function and Interaction
Personalis (United States)
2020-2025
University of California San Diego Medical Center
2018-2020
University of California, San Diego
2018-2020
Abstract Circulating tumor DNA (ctDNA) detection can predict clinical risk in early-stage tumors. However, applications are constrained by the sensitivity of clinically validated ctDNA approaches. NeXT Personal is a whole-genome-based, tumor-informed platform that has been analytically for ultrasensitive at 1–3 ppm with 99.9% specificity. Through an analysis 171 patients lung cancer from TRACERx study, we detected pre-operatively within 81% adenocarcinoma (LUAD), including 53% those...
Abstract Background Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer have revolutionized the treatment of tumors. The influence host germline genetics interaction tumor neoantigens remains poorly defined. We sought to determine between mutational burden (TMB) ability a patient’s major histocompatibility complex class...
Abstract Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates female and younger patients. Although responses differ with sex age, role MHC-based selection this context is unknown. We find individuals accumulate more poorly presented driver mutations than those older male patients,...
The major histocompatibility complex class I (MHC-I) molecule is a protein that displays intracellular peptides to T cells, allowing the immune system recognize and destroy infected or cancerous cells. MHC-I composed of highly polymorphic HLA-encoded alpha chain binds peptide Beta-2-microglobulin (B2M) acts as stabilizing scaffold. HLA mutations have been implicated mechanism evasion during tumorigenesis, B2M considered tumor suppressor gene. However, implications somatic not fully explored...
Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among most complex cancers. This complexity is paralleled by dozens mouse models that generate histologically similar but have not been systematically validated at level. Accurate pathogenesis HCC are essential for biomedical progress; therefore we compared genomic transcriptomic profiles four separate [MUP transgenic, TAK1-knockout, carcinogen-driven...
Abstract Purpose: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving tumors. We hypothesized multi-dimensional approach modeling both tumor and immune-related molecular would better ICB than simpler mutation-focused biomarkers, such as mutational burden (TMB). Experimental Design: Tumors from cohort patients with late-stage melanoma (n = 51) were profiled...
// Josette Northcott 1 , Gabor Bartha Jason Harris Conan Li Fabio C.P. Navarro Rachel Marty Pyke Manqing Hong Qi Zhang Shuyuan Ma Tina X. Chen Janet Lai Nitin Udar Juan-Sebastian Saldivar Erin Ayash Joshua Anderson Jiang Tiange Cui Tu Le Ruthie Chow Randy Jerel Velasco Chris Mallo Rose Santiago Robert C. Bruce Laurie J. Goodman Yi Dan Norton Richard O. * and John M. Lyle Personalis, Inc., Fremont, CA 94555, USA Co-last authors Correspondence to: Lyle, email: john.lyle@personalis.com...
Major histocompatibility complex (MHC)-bound peptides that originate from tumor-specific genetic alterations, known as neoantigens, are an important class of anticancer therapeutic targets. Accurately predicting peptide presentation by MHC complexes is a key aspect discovering therapeutically relevant neoantigens. Technological improvements in mass-spectrometry-based immunopeptidomics and advanced modeling techniques have vastly improved prediction over the past two decades. However,...
Major histocompatibility complex (MHC)–bound peptides that originate from tumor-specific genetic alterations, known as neoantigens, are an important class of anticancer therapeutic targets. Accurately predicting peptide presentation by MHC complexes is a key aspect discovering therapeutically relevant neoantigens. Technological improvements in mass spectrometry–based immunopeptidomics and advanced modeling techniques have vastly improved prediction over the past 2 decades. However,...
Abstract Circulating tumor DNA (ctDNA) is a non-invasive biomarker increasingly used to detect residual or recurrent disease and monitor patient response therapy. However, there need for more sensitive tests that can achieve earlier detection of disease. The NeXT Personal® Dx (NPDx) ctDNA MRD test uses paired normal whole genome sequencing (WGS) design bespoke panel up ∼1800 variants relies on advanced noise suppression ultrasensitive down ∼1 part per million (PPM) (1x10-6 fraction) with...
Abstract Human leukocyte antigen loss of heterozygosity (HLA LOH) allows cancer cells to escape immune recognition by deleting HLA alleles, causing the suppressed presentation tumor neoantigens. Despite its importance in immunotherapy response, few methods exist detect LOH, and their accuracy is not well understood. Here, we develop DASH (Deletion Allele-Specific HLAs), a machine learning-based algorithm LOH from paired tumor-normal sequencing data. With cell line mixtures, demonstrate...
ABSTRACT We describe the analytical validation of NeXT Personal ® , an ultra-sensitive, tumor-informed circulating tumor DNA (ctDNA) assay for detecting residual disease, monitoring therapy response, and recurrence in patients diagnosed with solid cancers. uses whole genome sequencing matched normal samples combined advanced analytics to accurately identify up ∼1,800 somatic variants specific patient’s tumor. A personalized panel is created, targeting these then used sequence cell-free...
Abstract Circulating tumor DNA (ctDNA) has enabled the non-invasive monitoring of molecular residual disease (MRD) which reflects therapeutic response/resistance prior to conventional imaging approaches. However, little is known about applications ctDNA in neoantigen-targeted personalized cancer vaccine setting, potentially due limited sensitivity current assays. NeXT Personal®, an ultra-sensitive tumor-informed assay was used longitudinally track advanced hepatocellular carcinoma (HCC)...
Abstract Tumor-informed liquid biopsy approaches have proven promising for detecting minimal residual disease (MRD) and recurrence of cancer following surgical resection or other therapy. However, current MRD assays typically detect ctDNA in a range above 30 to 300 parts per million (PPM), leaving significant fraction cases undetected, particularly soon after surgery early stage cancers where can be at very low levels. To address this, we developed NeXT Personal™, tumor-informed assay that...
e18030 Background: Human leukocyte antigen loss of heterozygosity (HLA LOH) restricts immune recognition tumors by limiting the major histocompatibility complex (MHC) presentation neoantigens to T cells and correlates with reduced response checkpoint blockade therapy (ICB) in non-small cell lung cancer. To explore mechanism behind impairment HLA LOH on ICB, we analyzed relationship between pathway, neoantigen ICB a head neck squamous carcinoma (HNSCC) cohort. Methods: Following baseline...
149 Background: MHC-1 molecules present intracellular peptides on the surface of tumor cells for recognition by CD8+ cytotoxic T-cells. Cancers with a high mutational burden (TMB) are more likely to respond immune checkpoint blockade (ICB) due increased chance having mutated peptide presented MHC-1. However, interaction between TMB and patient-specific ICB response is unknown. Methods: We analyzed 83 patients diverse solid tumors treated (tissue next generation sequencing (NGS) (Foundation...
6557 Background: The reduced scope, and number of genes profiled by typical liquid biopsy panels can result in missed biomarkers including neoantigens, which may change with treatment, as well potentially undetected resistance mechanisms pathways beyond the scope targets typically captured panels. To address these limitations, we used a whole-exome scale monitoring platform, NeXT Liquid Biopsy, to analyze head neck squamous cell carcinoma (HNSCC) patients that have received anti-PD1 therapy....
Abstract Checkpoint inhibitor therapy has demonstrated meaningful, if varied antitumor activity, with patient response influenced by a variety of biological factors, including complex interactions between the tumor and immune system. Thus, it is increasing interest to identify composite biomarkers integrating multiple features better predict immunotherapy response. In this study we use comprehensive immungenomics profiling platform examine effectiveness our neoantigen score for stratifying...
Abstract Major histocompatibility complex (MHC)-bound peptides that originate from tumor-specific genetic alterations, known as neoantigens, are an important class of anti-cancer therapeutic targets. Accurately predicting peptide presentation by MHC complexes is a key aspect discovering therapeutically relevant neoantigens. Technological improvements in mass-spectrometry-based immunopeptidomics and advanced modeling techniques have vastly improved prediction over the past two decades....
Abstract Human leukocyte antigen loss of heterozygosity (HLA LOH) allows cancer cells to escape immune recognition by deleting HLA alleles, causing the suppressed presentation tumor neoantigens that would otherwise bind them. Despite its importance in immunotherapy response, few methods exist detect LOH, and their accuracy is not well understood. Here, we develop DASH ( D eletion A llele- S pecific H LAs), a novel machine learning-based algorithm LOH from paired tumor-normal sequencing data....
Abstract Background Typical liquid biopsy panels capture a relatively small number of variants, and likely under-represent the heterogeneity resistance in late-stage cancers. This reduced scope can result overlooked therapeutic biomarkers which respond dynamically to treatment, as well potentially missed mechanisms pathway-level events. To address challenges associated with identifying multiple concurrent heterogeneous individual patients, we evaluated longitudinal whole exome sequencing...