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

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioas- say was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coil, 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 silica 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.

Automated summary

The ATLAS bioassay is developed to identify neoantigens empirically by expressing patient-specific tumor mutations individually, revealing both stimulatory and inhibitory responses. Therapeutic immunization with stimulatory neoantigens protected animals, while immunization with inhibitory responses resulted in accelerated tumor growth. Empirical testing shows that T-cell responses to neoantigens are more nuanced than straightforward MHC antigen recognition and could impact cancer immunotherapy design.