Cancer Immunogenomics: Computational Neoantigen Identification and Vaccine Design

Abstract

The application of modern high-throughput genomics to the study of cancer genomes has exploded in the past few years, yielding unanticipated insights into the myriad and complex combinations of genomic alterations that lead to the development of cancers. Coincident with these genomic approaches have been computational analyses that are capable of multiplex evaluations of genomic data toward specific therapeutic end points. One such approach is called “immunogenomics” and is now being developed to interpret protein-altering changes in cancer cells in the context of predicted preferential binding of these altered peptides by the patient’s immune molecules, specifically human leukocyte antigen (HLA) class I and II proteins. One goal of immunogenomics is to identify those cancer-specific alterations that are likely to elicit an immune response that is highly specific to the patient’s cancer cells following stimulation by a personalized vaccine. The elements of such an approach are outlined herein and constitute an emerging therapeutic option for cancer patients.

Patient-Specific Dendritic Cell Vaccines with Autologous Tumor Antigens in 72 Patients with Metastatic Melanoma

“…In recent years, evidence has accumulated suggesting that the best source of antigens for vaccines is autologous tumor because of unique neoantigens that result from nonsynonymous mutations [9,10]. Immunogenomics have made it possible to identify nonsynonymous mutations, determine messenger sequences that can be transcribed and translated, and predict the neoantigenicity and HLA-binding potential of specific molecules [11,12]. The best way to present such ATA may be on autologous DC rather than directly injecting antigens [13–15].…”

“…For several years, we conducted clinical trials with autologous DC loaded with ATA (DC–ATA) derived from short-term cell cultures and then admixed with GM–CSF at the time of injection [11,26–31]. The mechanism of action for this DC vaccine (DCV) is believed to be the induction of new immune responses to ATA or enhancement of weak existing immune responses.…”

The Community Oncology and Academic Medical Center Alliance in the Age of Precision Medicine: Cancer Genetics and Genomics Considerations

“…In the case of NGS, the sheer number of nucleotides reads, the task of aligning these reads to reference sequences, predicting functional consequences of genomic variation and the translation of these findings into clinically actionable information necessitated computational biological expertise [ 119 , 120 , 121 , 122 ]. Computational biological analysis now constitutes an integral element of the data workflow in precision oncology [ 123 , 124 , 125 , 126 ]; effective clinical translation depends inextricably upon the availability of these computational resources [ 127 , 128 , 129 , 130 ].…”

Current Strategies and Applications for Precision Drug Design

“…Finally, the predicted peptides are synthesized and tested for relating phenotypes using experimental assays. More comprehensive descriptions could be found in many excellent reviews ( Gubin et al, 2015 ; Schumacher and Schreiber, 2015 ; Hundal et al, 2016 ; Bethune and Joglekar, 2017 ). During the process of developing neoantigens, the accurate prediction of mutation associated neoantigens using computational methods is of great significance, which could accelerate the whole process and hence save much time and money.…”