High sensitivity of cancer exome-based CD8 T cell neo-antigen identification

Abstract

Recent data suggest that T-cell reactivity against tumor-specific neo-antigens may be central to the clinical efficacy of cancer immunotherapy. The development of personalized vaccines designed to boost T-cell reactivity against patient specific neo-antigens has been proposed largely on the basis of these findings. Work from several groups has demonstrated that novel tumor-specific antigens can be discovered through the use of cancer exome sequencing data, thereby providing a potential pipeline for the development of patient-specific vaccines. Importantly though, it has not been established which fraction of cancer neo-antigens that can be recognized by CD8+ T cells is successfully uncovered with the current exome-based epitope prediction strategies. Here, we use a data set comprising human cancer neo-antigens that was previously identified through the use of unbiased, computational-independent strategies to describe the potential of cancer exome-based neo-antigen discovery. This analysis shows a high sensitivity of exome-guided neo-antigen prediction of approximately 70%. We propose that future research should focus on the analysis and optimization of the specificity of neo-antigen prediction, and should undoubtedly entail the clinical evaluation of patient-specific vaccines with the aim of inducing immunoreactivity against tumor-displayed neo-antigens in a physiologically relevant context.

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

“…The lack of primary tumor also prevented the search for patient-specific neo-epitopes and CD8 + T cells recognizing such epitopes. 13 , 37 , 45 In ongoing research, we are looking for ways to evaluate the tumor-killing abilities of DRibble-responsive T cells in other cancer types where autologous tumor cells are available. Also, we aim to perform comparable monitoring studies in a cohort of patients in whom objective clinical responses were observed after therapy to determine whether the presence or magnitude of DRibble-responsive CD8 + T cells correlate with improved clinical outcome.…”

Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

“…27,[29][30][31] In subsequent studies in humans it has then been demonstrated that tumor sequencing data can also be exploited in a clinical setting, and that neoantigens serve as tumor-rejection antigens. 30,[32][33][34][35] As no standard treatment for metastatic NETs was established yet, and because NETs are known to be highly heterogeneous and unique regarding the genomic landscape, we suggest, that a personalized treatment strategy, targeting patient-specific neoantigens, might be an appropriate approach.…”

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

“…[79][80][81] Advances in DNA and RNA sequencing techniques led to the identification of mutant tumor-specific antigens (TSA, neo-Ags and neo-epitopes) with potential therapeutic capacity. [82][83][84][85] In an interesting study, a dendritic cell vaccine, tested in patients with advanced melanoma, induced neo-Agspecific T cells demonstrating that vaccination directed at tumor-encoded amino acid substitutions (mutations) broadens the antigenic breadth and clonal diversity of antitumor immunity. 86 In the field of cancer epitope vaccines, the modified, optimized or variant peptides, also known as altered peptide ligands (APLs), mimotopes, heteroclitic peptides or peptide analogs, bearing mutated versions of natural epitopes derived from TAAs are considered as promising candidates and were used to improve vaccine efficacy.…”