SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies.


Introduction
Immunotherapy has emerged as an important treatment strategy for patients with cancer. With several recent approvals by the U.S. Food and Drug Administration (FDA), cancer immunotherapy has become the latest addition to the toolbox of effective cancer treatments that includes chemotherapy, signal transduction inhibitors, anti-angiogenic agents, radiotherapy, and surgery.
Successful development and testing, regulatory approval and clinical application of cancer immunotherapies require the identification and validation of biomarkers of efficacy. The importance of reliable biomarkers to guide immune-based and personalized cancer therapies is clear. Biomarkers can aid in early disease diagnosis, help clinicians identify patients most likely to benefit from these expensive treatments, and facilitate drug discovery, development and biological/ clinical evaluation of cancer immunotherapies.
For over twenty-five years the Society for Immunotherapy of Cancer (SITC; formerly the International Society for Biological Therapy of Cancer, iSBTc) has advanced the science, development and application of biological therapy/immunotherapy of cancer. The society has long recognized the importance of biomarkers for cancer immunotherapy, which has been the focus of a number of SITC/iSBTc symposia and workshops [1][2][3][4][5], and has published recommendations [6] and summaries [7][8][9][10].
To support the efforts of investigators involved in research to identify and validate biomarkers for cancer immunotherapy, the authors and members of the SITC Biomarkers Taskforce have identified key biomarker references and online resources and organized these into this SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document. This document provides an overview of suggested publications and resources for studies on biomarkers for cancer immunotherapy. This resource document is divided into two sections: Part I: Immunotherapy Biomarker References; and Part II: High Throughput and New Technologies for Biomarker Discovery: Arrays, Platforms, Tools for The Bench and Online Resources. While many important references and resources in the field are included in this document, it does not intend to represent an exhaustive list of all relevant publications, products or resources in the growing, and important field of immune biomarkers. A comprehensive list of online tools for bioinformatics and molecular biology research is available from the Bioinformatics Links Directory [11,12].
A draft of the present document was originally provided to attendees of the SITC/iSBTc Symposium on Immuno-Oncology Biomarkers, 2010 and Beyond: Perspectives from the iSBTc Biomarker Task Force [1], which was held September 30, 2010 at the National Institutes of Health in conjunction with the society's 25th Annual Meeting. Following the symposium, the draft document was posted on the society's website for open comment. The comments were reviewed by the authors and incorporated into this manuscript. The references and online resources are organized as outlined in Table 1.

Examples
Clinical Laboratory Improvement Amendments (CLIA) Guideline: http://www.cms.hhs.gov/CLIA/: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) -common platform of Europe, Japan and United States authorities: http://www.ich.org/ products/guidelines.html Attig S, Price L, Janetzki S, Kalos M, Pride M, McNeil L, Clay T, Yuan J, Odunsi K, Hoos A, Romero P, Britten CM, Assay Working Group CC. A critical assessment for the value of markers to gate-out undesired events in HLA-peptide multimer staining protocols. J Transl Med, 9:108, 2011 Maecker

Examples
Name: Affymetrix Genome-Wide Human SNP Array 6.0 Comment:1.8 million genetic markers, including more than 906,600 single nucleotide polymorphisms (SNPs) and more than 946,000 probes for the detection of copy number variation Website:http://www.affymetrix.com/browse/products. jsp?productId=131533&navMode=34000 &navAction= jump&aId=productsNav#1_1 Name: Affymetrix DMET Plus Premier Pack Comment:Drug metabolism studies. Coverage of a wide range of genetic variations, including common and rare SNPs, insertions, deletions, tri-alleles, and copy number. 1,936 drug metabolism markers in 225 genes Website:http://www.affymetrix.com/browse/products. jsp?productId=131412&navMode=34000&navAction= jump&aId=productsNav#1_1 Name: Illumina Omni Microarray Comment:Next generation genome-wide association studies. The Omni family of microarrays will soon allow researchers to assay up to 5 million markers per sample, including comprehensive coverage of both common and rare variants identified by 1000 Genomes Project. As novel SNP sets are released into the public database, researchers using Omni products will have exclusive access to supplemental arrays that build up to the full 5 million variants Website:http://www.illumina.com/landing/click/gwas. ilmn?scid=2011110PPC1&gclid= CJij6ffe26kCFQPc4AodcmxEZQ Name: Fluidigm Dynamic Array for SNP Genotyping Comment:The Fluidigm Dynamic Arrays allow you to use your existing TaqMan ® SNP Genotyping assays in a flexible and cost effective fashion. Each dynamic array allows you to setup up to 9,216 individual TaqMan reactions in a single experiment Website:http://www.expressionanalysis.com/services/ category/fluidigm_dna_focused_set_snp Name: TaqMan ® Pre-Designed SNP Genotyping Assays Comment:Includes over 4.5 million SNP assays, including 3.5 million HapMap, and~70,000 coding SNP assays. This collection now includes~160,000 validated assays with associated minor allele frequency data available Website:https://products.appliedbiosystems.com/ab/en/ US/adirect/ab? cmd=catNavigate2&catID=600769&tab=TechSpec

B. Next Generation Sequencing Data Analysis
Blog Name: SEQanswers Comment:SEQanswers is a blog founded to be an information resource and user-driven community focused on all aspects of next-generation genomics. A reasonably thorough table of next-gen-seq software available in the commercial and public domain is provided Website:http://seqanswers.com/forums/showthread. php?t=43 Note: Examples Name: Cufflinks Comment:Cufflinks assembles transcripts, estimates their abundances, and tests for differential expression and regulation in RNA-Seq samples. It accepts aligned RNA-Seq reads and assembles the alignments into a parsimonious set of transcripts, free of charge Website:http://cufflinks.cbcb.umd.edu/ License needed:No Name: Bowtie Comment:Bowtie is an ultrafast, memory-efficient short read aligner. It aligns short DNA sequences (reads) to the human genome at a rate of over 25 million 35-bp reads per hour. Bowtie indexes the genome with a Burrows-Wheeler index to keep its memory footprint small: typically about 2.2 GB for the human genome (2.9 GB for paired-end). Data on transcription factors, their experimentally-proven binding sites, and regulated genes. Its broad compilation of binding sites allows the derivation of positional weight matrices Website:http://www.gene-regulation.com/pub/databases.html Name: OptiTope Comment:OptiTope aims at assisting immunologists in designing epitope-based vaccines. It is an easy-to-use tool to determine a provably optimal set of epitopes with respect to overall immunogenicity in a specific individual or a target population, free of charge Website:http://www.epitoolkit.org/optitope Name: Cancer Central Clinical Database (C3D) Comment:Cancer Central Clinical Database (C3D) is a clinical trials data management system. C3D collects clinical trial data using standard case report forms (CRFs) based on common data elements (CDEs) Website:https://cabig.nci.nih.gov/tools/c3d Name: UCSC Genome Browser Comment:Provides a large database of publicly available sequence and annotation data along with an integrated tool set for examining and comparing the genomes of organisms, aligning sequence to genomes, and displaying and sharing users' own annotation data Website:http://genome.ucsc.edu/ Name: Next Bio Comment:Exhaustive collection of public microarray data. NextBio's platform combines powerful tools with unique correlated content. With NextBio you can search tens of thousands of studies containing billions of data points spanning different experimental platforms, organisms and data types Website:http://www.nextbio.com/b/corp/faq.nb Name: SYFPEITHI Comment:SYFPEITHI is a database comprising more than 7,000 peptide sequences known to bind class I and

Conclusion
Immune biomarkers are playing an increasingly important role in the successful development, clinical evaluation, and immune monitoring of cancer immunotherapies. The references, products and online resources in this Cancer Immunotherapy Biomarkers Resource Document were identified by the authors and the SITC/iSBTc Taskforce on Immunotherapy Biomarkers to support the discovery, evaluation and application of biomarkers for cancer immunotherapy. These selected references and links serve as a compass to point investigators to useful resources in this ever growing, and important field of cancer immunotherapy biomarkers. Emerging issues surrounding cancer immunotherapy biomarker discovery and clinical application will continue to be addressed in upcoming SITC Annual Meetings and Associated Programs [13].