Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.

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Abstract

Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.

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The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

Aaron McKenna, Matthew Hanna, Eric Banks … (2010)

Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS--the 1000 Genome pilot alone includes nearly five terabases--make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis calculations from common data management infrastructure enables us to optimize the GATK framework for correctness, stability, and CPU and memory efficiency and to enable distributed and shared memory parallelization. We highlight the capabilities of the GATK by describing the implementation and application of robust, scale-tolerant tools like coverage calculators and single nucleotide polymorphism (SNP) calling. We conclude that the GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.

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Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Martin Reck, Delvys Rodriguez-Abreu, Andrew G Robinson … (2016)

Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).

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Author and article information

Journal

Journal ID (iso-abbrev): Ann Oncol

Title: Annals of oncology : official journal of the European Society for Medical Oncology

Publisher: Oxford University Press (OUP)

ISSN (Electronic): 1569-8041

ISSN (Print): 0923-7534

Publication date (Electronic): Jan 01 2019

Volume: 30

Issue: 1

Affiliations

[1 ] Human Oncology and Pathogenesis Program; The Immunogenomics and Precision Oncology Program, Memorial Sloan Kettering Cancer Center, New York. Electronic address: chant@mskcc.org.

[2 ] Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA.

[3 ] Translational Cancer Therapeutics Laboratory, Francis Crick Institute, London.

[4 ] Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.

[5 ] Institute of Pathology, University Hospital Heidelberg, Heidelberg; Germany and German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany.

[6 ] Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Electronic address: solange.peters@chuv.ch.

Article

Publisher Item ID: S0923-7534(19)30997-4

DOI: 10.1093/annonc/mdy495

PMC ID: 6336005

PubMed ID: 30395155

SO-VID: e3878dc7-a3cd-4cdf-9219-2d4298a57671

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