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 - Funding Information:
H. Lam reports a patent for PCT/US18/23442 pending. L.K. McNeil reports patents for PCT/US18/23442 and PCT/US20/33277 pending to Genocea Biosciences. R.B. Cohen reports grants and personal fees from Genocea Biosciences during the conduct of the study; and grants and personal fees from HEAT Biologics outside the submitted work. M.L. Johnson reports grants from Genocea Biosciences during the conduct of the study; and personal fees from Otsuka and Astel-las Pharma, grants and other from Genentech/Roche, Boehringer Ingelheim, AstraZeneca, Calithera Biosciences, Merck, Loxo, Sanofi, Mirati Therapeutics, Pfizer, Guardant Health, Incyte, AbbVie, Atreca, GlaxoSmithKline, Gritstone Oncology, Janssen, Lilly, Novartis, Amgen, Daiichi Sankyo, EMD Serono, and WindMIL, other from Ribon Therapeutics, Achillies Therapeutics, Association of Community Cancer Centers, Bristol-Myers Squibb, and G1 Therapeutics, and grants from Kadmon, Genmab, Stem CentRx, Checkpoint Therapeutics, Array BioPharma, Regeneron, Hengrui Pharmaceuticals, Lycera, BeiGene, Tarveda Therapeutics, CytomX Therapeutics, Dynavax, Corvus Pharmaceuticals, Genocea Biosciences, Adaptim-mune, Syndax, Neovia Oncology, Acerta Pharma, Takeda, Shattuck Labs, Apexigen, Atreca, OncoMed, Immunocore, Jounce Therapeutics, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Tmunity Therapeutics, and Seven and Eight Biopharmaceuticals outside the submitted work. M.L. Gillison reports other from Genocea Biosciences during the conduct of the study; and personal fees from Gilead, EMD Serono, BMS, Kura, Shattuck Labs, Bayer Healthcare, Roche, BioNTech AG, Merck, and NewLink Corporation and other from BMS, Kura, and Bicara Therapeutics outside the submitted work. M.N. Stein reports grants from Genocea Biosciences during the conduct of the study; and grants from Exelixis, Tmunity, Seattle Genetics, Nektar, Lilly, Bristol Myers Squibb, Harpoon, and Janssen Oncology outside the submitted work. U.N. Vaishampayan reports grants and personal fees from BMS, Inc., and Alkermes, and personal fees from Exelixis, Bayer, Pfizer, Merck, and Onc Live outside the submitted work. A.P. DeCillis reports personal fees from Genocea Biosciences, Exelixis, Osmol, Cybrexa, Codiak, Monopteros, Pyramid, and Evelo outside the submitted work. J.J. Foti reports other from Genocea Biosciences during the conduct of the study. W. Broom reports a patent for PCT/ US18/23442 pending; in addition, W. Broom was an employee of Genocea Biosciences at the time of his contribution to this article. E.M. Jaffee reports personal fees from Genocea Biosciences during the conduct of the study; and personal fees from CSTONE, Achilles, Adaptive Biotech, dragonfly, and Parker Institute, grants from Lust-garten Foundation outside the submitted work. K.-K Wong is a founder and equity holder of G1 Therapeutics and has consulting and sponsored research with AstraZeneca, Janssen, Pfizer/Array Biop-harma, Novartis, Merck, Zentalis, and Genocea Biosciences as well as sponsored research (only) with Takeda, BMS, Mirati, Alkermes, Merus, Amgen, Ansun Biopharma, Eliven Therapeutics, Tvardi Therapeutics, Delfi Diagnostics, and Dracen Pharmaceuticals. C.G. Drake reports other from Genocea Biosciences during the conduct of the study; and other from Bayer, BMS, Compugen, F-Star, Kleo, Merck, Merck-Serono, Pfizer, Roche/Genentech, Shattuck Labs, Tizona, and Werewolf outside the submitted work; in addition, C.G. Drake had a patent for LAG-3 issued and licensed to BMS. P.M. Carroll reports a patent for PCT/US18/23442 pending. T.A. Davis reports personal fees and other from Genocea Biotherapeutics during the conduct of the study; and personal fees and other from Genocea Biosciences outside the submitted work. J.B. Flechtner reports personal fees and other from Genocea Biosciences outside the submitted work; in addition, J.B. Flechtner had patents for PCT/US18/23442 and PCT/ US20/033277 pending to Genocea Biosciences. No disclosures were reported by the other authors.
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 -