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.

• Authors: Hubert Lam, Lisa K McNeil, Hanna Starobinets, Victoria L DeVault, Roger B Cohen, Przemyslaw Twardowski, Melissa L Johnson, Maura L Gillison, Mark N Stein, Ulka N Vaishampayan, Arthur P DeCillis, James J Foti, Vijetha Vemulapalli, Emily Tjon, Kyle Ferber, Daniel B DeOliveira, Wendy Broom, Parul Agnihotri, Elizabeth M Jaffee, Kwok-Kin Wong, Charles G Drake, Pamela M Carroll, Thomas A Davis, Jessica Baker Flechtner
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 3 Pg. 696-713 (03 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 33504579 (Publication Type: Journal Article)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• Cancer Vaccines

Topics

• Animals
• Antigens, Neoplasm (genetics, immunology)
• Biomarkers, Tumor (genetics, immunology)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Line, Tumor
• Clinical Trials as Topic
• DNA Mutational Analysis
• Disease Models, Animal
• Disease Progression
• Genomics (methods)
• Humans
• Immunity, Cellular
• Immunogenicity, Vaccine
• Melanoma, Experimental
• Mice
• Mutation
• Neoplasms (genetics, immunology, pathology, therapy)
• T-Lymphocytes (immunology, metabolism, pathology)
• Treatment Outcome
• Vaccination