From the Guest Editor.

A renaissance in immunotherapy spearheaded by the clinical successes of immune checkpoint blockade and adoptive cellular therapy has led to a reinvigoration of interest in the field of tumor antigen discovery as more targets are revealed and clinically effective means of targeting individual tumors can now be implemented. The confluence of mass spectrometry (MS), already well established in epitope discovery, and next-generation sequencing (NGS), a more recent tool for comprehensive genetic profiling of individual patient tumors, provides a rich substrate for analytics mining, algorithm development, and empiric validation. A rapidly increasing repository of potential immunogenic epitopes and their source antigen can now render antigen-specific–based immunotherapy into a potential therapeutic modality for not only melanoma but also a broad range of solid tumor malignancies and for greater numbers of patients with cancer. The term “neoantigen,” conventionally defined as an antigen associated with a mutated epitope, has been appropriated here for the broader inclusion of all novel tumor-associated antigens, whether mutated, or overexpressed but not mutated, or tissue restricted, tumor-associated antigens. To be precise, “neo,” which can be interpreted as “new in nature” (i.e., mutated) proteins, may alternatively be ascribed to “novel” in the sense of a previously undiscovered antigen; it is in this more inclusive context that these chapters are presented. Because of the ability to analyze individual patient’s tumor, a “personalized” approach to immunebased therapy has been advocated; depending on mutational load and other factors, dozens to several hundred “personal/private”mutated neoepitopes can be divined from whole exome or RNAseq analysis of patient tumors, the attraction being the possibility that such personalized/mutated neoepitopes are more immunogenic and, in some cases, represent driver mutations. In the chapter by Dr Mardis, an overview of NGS methods accompanied by in-depth consideration of the advantages and challenges of various cutting-edge approaches is presented. This strategy is balanced by the method of MS developed by Dr. Rammensee (who authors the chapter) to characterize peptides eluted from surfaceMHC. In contrast to NGS-based methods, MS-based analysis captures higher-abundance epitopes and is also more likely to yield shared nonmutated target antigens. In someways, this MS-based approach recapitulates the very early work performed by van den Eynde and Boon, whereby HLA-matched targets expressing tumorderived cDNA libraries were probed using a previously generated tumor-reactive CTL clone to identify the target gene. Both these approaches require some type of functional readout, CTL killing in the former and, in the latter, epitope presentation, which provides greater confidence that theMS-sequenced peptide is presented by surface MHC and therefore likely to be a valid target. To address, in part, the issue of RNAseq versusMS-based targets, theMcIntosh group draws on the CPTAC database in an attempt to answer the question of whether abundant genes identified by RNAseq are concordant with epitopes identified in MS-based assays and makes a strong case for a “large intersection” between abundant proteins as measured byMS and abundant transcripts measured by RNAseq. More important is the (unanswered) question of whether mutated, generally lower abundance epitopes, or nonmutated, tissue-restricted but higher-abundance epitopes (e.g., cancer-testis antigens) are more immunogenic. In practice, both approaches are complementary: MS can be used to confirm epitopes identified by NGS-based analysis using synthetic peptides corresponding to the epitope of interest and conversely RNAseq used to confirm overexpression of peptides identified by MS-based analysis. Application of these approaches to hematologic malignancies is reviewed by DrWu, whose chapter provides a comprehensive annotation of various antigen identification strategies and intracellular, as well as surface target antigens for acute and chronic leukemia and myeloma. Dr Dunn provides similar treatment for glioblastoma, a solid tumor malignancy that is almost uniformly fatal and for which vigorous efforts are being made to develop immune-based approaches. Finally, the clinical implications of antigen discovery are considered in the form of dendritic cell vaccination and T cell–based therapies. Dr Bhardwaj examines strategies to enhance DC vaccination, considerations for use of dendritic cell subsets, adjuvants, and both in vitro and in vivo antigen delivery methods. Dr Robbins’ review cites numerous exciting examples using tumor-infiltrating lymphocyte cultures not only as a tool for defining neoantigens associated with nonmelanoma malignancies, but also a powerful demonstration of targeted therapy when tumor-infiltrating lymphocytes are enriched for desired neoantigen specificities. In the