TY - JOUR
T1 - An empirical antigen selection method identifies neoantigens that either elicit broad antitumor t-cell responses or drive tumor growth
AU - Lam, Hubert
AU - McNeil, Lisa K.
AU - Starobinets, Hanna
AU - Devault, Victoria L.
AU - Cohen, Roger B.
AU - Twardowski, Przemyslaw
AU - Johnson, Melissa L.
AU - Gillison, Maura L.
AU - Stein, Mark N.
AU - Vaishampayan, Ulka N.
AU - Decillis, Arthur P.
AU - Foti, James J.
AU - Vemulapalli, Vijetha
AU - Tjon, Emily
AU - Ferber, Kyle
AU - Deoliveira, Daniel B.
AU - Broom, Wendy
AU - Agnihotri, Parul
AU - Jaffee, Elizabeth M.
AU - Wong, Kwok Kin
AU - Drake, Charles G.
AU - Carroll, Pamela M.
AU - Davis, Thomas A.
AU - Flechtner, Jessica Baker
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - 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 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.
AB - 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 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.
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U2 - 10.1158/2159-8290.CD-20-0377
DO - 10.1158/2159-8290.CD-20-0377
M3 - Article
C2 - 33504579
AN - SCOPUS:85102704481
SN - 2159-8274
VL - 11
SP - 696
EP - 713
JO - Cancer discovery
JF - Cancer discovery
IS - 3
ER -