An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth

Abstract

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. Significance: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521

Integrating CD4 + T cell help for therapeutic cancer vaccination in a preclinical head and neck cancer model

“…The robustness of personalized cancer vaccination therapy is greatly influenced by antigen selection. 27 , 28 Use of SLPs that includes predicted high-affinity MHC-I epitopes is an established format for cancer vaccination. 18 In addition to TSAs from somatically mutated proteins, TAAs from over-expressed proteins or from ERVs constitute additional targets.…”

Single-Cell TCR and Transcriptome Analysis: An Indispensable Tool for Studying T-Cell Biology and Cancer Immunotherapy

“…The mutated peptides can be processed and presented by MHC molecules, and then the peptide/MHC complexes can be recognized by T cells. The presence of neoantigen-reactive T cells have been identified across different cancer histology, like lung cancer ( 41 , 42 ) bladder cancer ( 43 ), head and neck cancer ( 44 , 45 ), ovarian cancer ( 46 – 49 ) pancreatic cancer ( 50 , 51 ) and gastrointestinal epithelial malignancies ( 35 , 52 – 54 ). Interestingly, the T cells identified in these studies recognized unique somatic mutations, with few exceptions where the T cells recognized hot spot mutations on oncogenes, like KRAS ( 55 , 56 ) and p53 ( 9 , 47 , 48 , 54 ).…”

Vaccines for Non-Viral Cancer Prevention

“…Studies of in vitro priming on cells derived from healthy donors are key in preventive vaccines as they give information on whether a determinate antigen is capable of being immunogenic without previous contact. An interesting novel method for these studies is the Genocea's ATLASTM bioassay, where autologous APCs expressing every predicted peptide (using Escherichia coli) are incubated with autologous PBMC-derived T-cells to assess cytokine production and validate their immunogenicity [103].…”