A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer

Patrick A. Ott; Siwen Hu-Lieskovan; Bartosz Chmielowski; Ramaswamy Govindan; Aung Naing; Nina Bhardwaj; Kim Margolin; Mark M. Awad; Matthew D. Hellmann; Jessica J. Lin; Terence Friedlander; Meghan E. Bushway; Kristen N. Balogh; Tracey E. Sciuto; Victoria Kohler; Samantha J. Turnbull; Rana Besada; Riley R. Curran; Benjamin Trapp; Julian Scherer; Asaf Poran; Dewi Harjanto; Dominik Barthelme; Ying Sonia Ting; Jesse Z. Dong; Yvonne Ware; Yuting Huang; Zhengping Huang; Amy Wanamaker; Lisa D. Cleary; Melissa A. Moles; Kelledy Manson; Joel Greshock; Zakaria S. Khondker; Ed Fritsch; Michael S. Rooney; Mark DeMario; Richard B. Gaynor; Lakshmi Srinivasan

doi:10.1016/j.cell.2020.08.053

A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer

Patrick A. Ott, Siwen Hu-Lieskovan, Bartosz Chmielowski, Ramaswamy Govindan, Aung Naing, Nina Bhardwaj, Kim Margolin, Mark M. Awad, Matthew D. Hellmann, Jessica J. Lin, Terence Friedlander, Meghan E. Bushway, Kristen N. Balogh, Tracey E. Sciuto, Victoria Kohler, Samantha J. Turnbull, Rana Besada, Riley R. Curran, Benjamin Trapp, Julian SchererAsaf Poran, Dewi Harjanto, Dominik Barthelme, Ying Sonia Ting, Jesse Z. Dong, Yvonne Ware, Yuting Huang, Zhengping Huang, Amy Wanamaker, Lisa D. Cleary, Melissa A. Moles, Kelledy Manson, Joel Greshock, Zakaria S. Khondker, Ed Fritsch, Michael S. Rooney, Mark DeMario, Richard B. Gaynor, Lakshmi Srinivasan

Research output: Contribution to journal › Article › peer-review

207 Scopus citations

Abstract

In a phase Ib clinical trial, Ott et al. demonstrate feasibility, safety, and immunogenicity of the combination of personalized neoantigen vaccines and PD-1 inhibition in patients with advanced solid tumors. Vaccine-induced T cells persist over time, exhibit cytotoxic potential, and can migrate to tumors. Epitope spread and major pathologic tumor responses were detected following vaccination.

Original language	English
Pages (from-to)	347-362.e24
Journal	Cell
Volume	183
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2020.08.053
State	Published - Oct 15 2020

Keywords

NEO-PV-01
T cell
anti-PD-1
cancer vaccine
checkpoint inhibitor
epitope spread
immunotherapy
metastatic cancer
neoantigen
personalized vaccine

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10.1016/j.cell.2020.08.053

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Ott, P. A., Hu-Lieskovan, S., Chmielowski, B., Govindan, R., Naing, A., Bhardwaj, N., Margolin, K., Awad, M. M., Hellmann, M. D., Lin, J. J., Friedlander, T., Bushway, M. E., Balogh, K. N., Sciuto, T. E., Kohler, V., Turnbull, S. J., Besada, R., Curran, R. R., Trapp, B., ... Srinivasan, L. (2020). A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer. Cell, 183(2), 347-362.e24. https://doi.org/10.1016/j.cell.2020.08.053

@article{93ab841fbc5c4b9cb37bd8c9c37ce4f5,

title = "A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer",

abstract = "In a phase Ib clinical trial, Ott et al. demonstrate feasibility, safety, and immunogenicity of the combination of personalized neoantigen vaccines and PD-1 inhibition in patients with advanced solid tumors. Vaccine-induced T cells persist over time, exhibit cytotoxic potential, and can migrate to tumors. Epitope spread and major pathologic tumor responses were detected following vaccination.",

keywords = "NEO-PV-01, T cell, anti-PD-1, cancer vaccine, checkpoint inhibitor, epitope spread, immunotherapy, metastatic cancer, neoantigen, personalized vaccine",

author = "Ott, {Patrick A.} and Siwen Hu-Lieskovan and Bartosz Chmielowski and Ramaswamy Govindan and Aung Naing and Nina Bhardwaj and Kim Margolin and Awad, {Mark M.} and Hellmann, {Matthew D.} and Lin, {Jessica J.} and Terence Friedlander and Bushway, {Meghan E.} and Balogh, {Kristen N.} and Sciuto, {Tracey E.} and Victoria Kohler and Turnbull, {Samantha J.} and Rana Besada and Curran, {Riley R.} and Benjamin Trapp and Julian Scherer and Asaf Poran and Dewi Harjanto and Dominik Barthelme and Ting, {Ying Sonia} and Dong, {Jesse Z.} and Yvonne Ware and Yuting Huang and Zhengping Huang and Amy Wanamaker and Cleary, {Lisa D.} and Moles, {Melissa A.} and Kelledy Manson and Joel Greshock and Khondker, {Zakaria S.} and Ed Fritsch and Rooney, {Michael S.} and Mark DeMario and Gaynor, {Richard B.} and Lakshmi Srinivasan",

note = "Funding Information: We thank all of the patients and their families who participated in the study. We are grateful to all of the members of Neon Therapeutics/BioNTech US for support of and assistance in the study. We thank April Lamb and Jennifer Tepper for clinical operations; Marc Wolfgang, Scott White, Stephen Crimlisk, and Yeimy Garcia for technical operations; Jonathan McGee, Brian Sullivan, Daniel Kallin, Jeff Zhang, Amanda Aldous, and Robyn Eisert for peptide synthesis and manufacturing process development; Janani Sridar and Paul Turcott for tetramer reagent generation; Myranda Maynard and Sagar Chhangawala for bioinformatics support; Kerry Chios and John Curran for lab operation support and biobank management; and Hugh O'Dowd for support and guidance on the study. We thank Bristol-Myers Squibb for the nivolumab supply. The study was sponsored by Neon Therapeutics/BioNTech US. This manuscript is dedicated to our late colleague, Ying Sonia Ting. Conceptualization and Implementation of the Study, P.A.O. L.S. R.G. E.F. and J.G. Clinical Investigators on the Study, P.A.O. S.H.-L. B.C. R.G. A.N. N.B. K.M. M.M.A. M.D.H. J.J.L. and T.F. Biomarker and Sequencing Analysis, M.E.B. K.N.B. T.E.S. A.P. D.H. Y.S.T. and M.S.R. Patient Immune Analysis, V.K. S.J.T. R.B. R.R.C. K.N.B. and B.T. TCR Sequencing and Analysis, R.B. J.S. A.P. and Y.S.T. Peptide Synthesis and Purification, J.Z.D. Y.W. and Y.H. Tetramer Reagent Generation, D.B. Informatics Support and Clinical Data Management, Z.H. and A.W. Clinical Operations and Program Management, L.D.C. M.A.M. and K.M. Biostatistics Support, J.G. and Z.S.K. Medical Monitor on the Study, M.D. Manuscript Preparation (with input from all of the authors), P.A.O. L.S. R.B.G. M.D. Z.S.K. and M.S.R. P.A.O.: research funding paid to the institution—Bristol-Myers Squibb, Merck, AstraZeneca, Celldex, CytomX, GlaxoSmithKline, ARMO Biosciences, Neon Therapeutics; consultant—Array, Bristol-Myers Squibb, Merck, Genentech, Pfizer, Novartis, Neon Therapeutics, CytomX, Celldex. S.H.-L.: consultant—Amgen, Bristol-Myers Squibb, Genmab, Xencor; research support—Bristol-Myers Squibb, Merck, and Vaccinex. B.C.: member of the speakers{\textquoteright} bureaus for Regeneron and Sanofi. R.G.: advisory board member—Achilles; consultant—Horizon Pharma (spouse), GenePlus. A.N.: research funding from NCI, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse); advisory board member—CytomX Therapeutics, Novartis, Kymab, and Genome; travel and accommodation expense—ARMO BioSciences. N.B.: scientific advisory board member—Checkpoint Sciences, Curevac, Primevax, Novartis, Avidea, BI, Rome Therapeutics, Neon Therapeutics, Roche, and Genentech. Extramural member of the Parker Institute for Cancer Immunotherapy, K.M.: advisory boards or consultant—Nektar, ImaginAb, Neoleukin, and Akrevia; DSMB—IOvance. M.M.A.: research grants—Genentech, Bristol-Myers Squibb, AstraZeneca, Lilly; consultant—Genentech, Bristol-Myers Squibb, AstraZeneca, Merck, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, and Neon Therapeutics, M.D.H.: research funding—Bristol-Myers Squibb; consultant—Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Immunai, and Shattuck Labs; travel support/honoraria—AstraZeneca, Eli Lilly, Merck, and Bristol-Myers Squibb; and a patent has been filed by MSK related to the use of tumor mutation burden to predict the response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. J.J.L.: honoraria/consultant—Pfizer, C4 Therapeutics, Nuvalent, and Genentech; institutional research funding—Neon, Hengrui Therapeutics, Turning Point Therapeutics, and Novartis; travel fees—Pfizer; CME funding—OncLive. T.F.: research funding—Janssen; research funding to the institute—Seattle Genetics, Incyte, Bristol-Myers Squibb, Neon Therapeutics, and Roche/Genentech. R.B.G.: board of directors—Alkermes plc and Infinity Pharmaceuticals; scientific advisory board—Leap Therapeutics; stockholder and employee—Neon Therapeutics/BioNTech US. Stockholder and either current or past employees of Neon Therapeutics/BioNTech US: M.E.B. K.N.B. T.E.S. V.K. S.J.T. R.B. R.R.C. B.T. J.S. A.P. D.H. D.B. Y.S.T. J.Z.D. Y.W. Y.H. Z.H. A.W. L.D.C. M.A.M. K.M. J.G. Z.S.K. M.S.R. M.D. E.F. and L.S. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = oct,

day = "15",

doi = "10.1016/j.cell.2020.08.053",

language = "English",

volume = "183",

pages = "347--362.e24",

journal = "Cell",

issn = "0092-8674",

number = "2",

}

Ott, PA, Hu-Lieskovan, S, Chmielowski, B, Govindan, R, Naing, A, Bhardwaj, N, Margolin, K, Awad, MM, Hellmann, MD, Lin, JJ, Friedlander, T, Bushway, ME, Balogh, KN, Sciuto, TE, Kohler, V, Turnbull, SJ, Besada, R, Curran, RR, Trapp, B, Scherer, J, Poran, A, Harjanto, D, Barthelme, D, Ting, YS, Dong, JZ, Ware, Y, Huang, Y, Huang, Z, Wanamaker, A, Cleary, LD, Moles, MA, Manson, K, Greshock, J, Khondker, ZS, Fritsch, E, Rooney, MS, DeMario, M, Gaynor, RB & Srinivasan, L 2020, 'A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer', Cell, vol. 183, no. 2, pp. 347-362.e24. https://doi.org/10.1016/j.cell.2020.08.053

TY - JOUR

T1 - A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer

AU - Ott, Patrick A.

AU - Hu-Lieskovan, Siwen

AU - Chmielowski, Bartosz

AU - Govindan, Ramaswamy

AU - Naing, Aung

AU - Bhardwaj, Nina

AU - Margolin, Kim

AU - Awad, Mark M.

AU - Hellmann, Matthew D.

AU - Lin, Jessica J.

AU - Friedlander, Terence

AU - Bushway, Meghan E.

AU - Balogh, Kristen N.

AU - Sciuto, Tracey E.

AU - Kohler, Victoria

AU - Turnbull, Samantha J.

AU - Besada, Rana

AU - Curran, Riley R.

AU - Trapp, Benjamin

AU - Scherer, Julian

AU - Poran, Asaf

AU - Harjanto, Dewi

AU - Barthelme, Dominik

AU - Ting, Ying Sonia

AU - Dong, Jesse Z.

AU - Ware, Yvonne

AU - Huang, Yuting

AU - Huang, Zhengping

AU - Wanamaker, Amy

AU - Cleary, Lisa D.

AU - Moles, Melissa A.

AU - Manson, Kelledy

AU - Greshock, Joel

AU - Khondker, Zakaria S.

AU - Fritsch, Ed

AU - Rooney, Michael S.

AU - DeMario, Mark

AU - Gaynor, Richard B.

AU - Srinivasan, Lakshmi

N1 - Funding Information: We thank all of the patients and their families who participated in the study. We are grateful to all of the members of Neon Therapeutics/BioNTech US for support of and assistance in the study. We thank April Lamb and Jennifer Tepper for clinical operations; Marc Wolfgang, Scott White, Stephen Crimlisk, and Yeimy Garcia for technical operations; Jonathan McGee, Brian Sullivan, Daniel Kallin, Jeff Zhang, Amanda Aldous, and Robyn Eisert for peptide synthesis and manufacturing process development; Janani Sridar and Paul Turcott for tetramer reagent generation; Myranda Maynard and Sagar Chhangawala for bioinformatics support; Kerry Chios and John Curran for lab operation support and biobank management; and Hugh O'Dowd for support and guidance on the study. We thank Bristol-Myers Squibb for the nivolumab supply. The study was sponsored by Neon Therapeutics/BioNTech US. This manuscript is dedicated to our late colleague, Ying Sonia Ting. Conceptualization and Implementation of the Study, P.A.O. L.S. R.G. E.F. and J.G. Clinical Investigators on the Study, P.A.O. S.H.-L. B.C. R.G. A.N. N.B. K.M. M.M.A. M.D.H. J.J.L. and T.F. Biomarker and Sequencing Analysis, M.E.B. K.N.B. T.E.S. A.P. D.H. Y.S.T. and M.S.R. Patient Immune Analysis, V.K. S.J.T. R.B. R.R.C. K.N.B. and B.T. TCR Sequencing and Analysis, R.B. J.S. A.P. and Y.S.T. Peptide Synthesis and Purification, J.Z.D. Y.W. and Y.H. Tetramer Reagent Generation, D.B. Informatics Support and Clinical Data Management, Z.H. and A.W. Clinical Operations and Program Management, L.D.C. M.A.M. and K.M. Biostatistics Support, J.G. and Z.S.K. Medical Monitor on the Study, M.D. Manuscript Preparation (with input from all of the authors), P.A.O. L.S. R.B.G. M.D. Z.S.K. and M.S.R. P.A.O.: research funding paid to the institution—Bristol-Myers Squibb, Merck, AstraZeneca, Celldex, CytomX, GlaxoSmithKline, ARMO Biosciences, Neon Therapeutics; consultant—Array, Bristol-Myers Squibb, Merck, Genentech, Pfizer, Novartis, Neon Therapeutics, CytomX, Celldex. S.H.-L.: consultant—Amgen, Bristol-Myers Squibb, Genmab, Xencor; research support—Bristol-Myers Squibb, Merck, and Vaccinex. B.C.: member of the speakers’ bureaus for Regeneron and Sanofi. R.G.: advisory board member—Achilles; consultant—Horizon Pharma (spouse), GenePlus. A.N.: research funding from NCI, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse); advisory board member—CytomX Therapeutics, Novartis, Kymab, and Genome; travel and accommodation expense—ARMO BioSciences. N.B.: scientific advisory board member—Checkpoint Sciences, Curevac, Primevax, Novartis, Avidea, BI, Rome Therapeutics, Neon Therapeutics, Roche, and Genentech. Extramural member of the Parker Institute for Cancer Immunotherapy, K.M.: advisory boards or consultant—Nektar, ImaginAb, Neoleukin, and Akrevia; DSMB—IOvance. M.M.A.: research grants—Genentech, Bristol-Myers Squibb, AstraZeneca, Lilly; consultant—Genentech, Bristol-Myers Squibb, AstraZeneca, Merck, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, and Neon Therapeutics, M.D.H.: research funding—Bristol-Myers Squibb; consultant—Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Immunai, and Shattuck Labs; travel support/honoraria—AstraZeneca, Eli Lilly, Merck, and Bristol-Myers Squibb; and a patent has been filed by MSK related to the use of tumor mutation burden to predict the response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. J.J.L.: honoraria/consultant—Pfizer, C4 Therapeutics, Nuvalent, and Genentech; institutional research funding—Neon, Hengrui Therapeutics, Turning Point Therapeutics, and Novartis; travel fees—Pfizer; CME funding—OncLive. T.F.: research funding—Janssen; research funding to the institute—Seattle Genetics, Incyte, Bristol-Myers Squibb, Neon Therapeutics, and Roche/Genentech. R.B.G.: board of directors—Alkermes plc and Infinity Pharmaceuticals; scientific advisory board—Leap Therapeutics; stockholder and employee—Neon Therapeutics/BioNTech US. Stockholder and either current or past employees of Neon Therapeutics/BioNTech US: M.E.B. K.N.B. T.E.S. V.K. S.J.T. R.B. R.R.C. B.T. J.S. A.P. D.H. D.B. Y.S.T. J.Z.D. Y.W. Y.H. Z.H. A.W. L.D.C. M.A.M. K.M. J.G. Z.S.K. M.S.R. M.D. E.F. and L.S. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - In a phase Ib clinical trial, Ott et al. demonstrate feasibility, safety, and immunogenicity of the combination of personalized neoantigen vaccines and PD-1 inhibition in patients with advanced solid tumors. Vaccine-induced T cells persist over time, exhibit cytotoxic potential, and can migrate to tumors. Epitope spread and major pathologic tumor responses were detected following vaccination.

AB - In a phase Ib clinical trial, Ott et al. demonstrate feasibility, safety, and immunogenicity of the combination of personalized neoantigen vaccines and PD-1 inhibition in patients with advanced solid tumors. Vaccine-induced T cells persist over time, exhibit cytotoxic potential, and can migrate to tumors. Epitope spread and major pathologic tumor responses were detected following vaccination.

KW - NEO-PV-01

KW - T cell

KW - anti-PD-1

KW - cancer vaccine

KW - checkpoint inhibitor

KW - epitope spread

KW - immunotherapy

KW - metastatic cancer

KW - neoantigen

KW - personalized vaccine

UR - http://www.scopus.com/inward/record.url?scp=85092455165&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.08.053

DO - 10.1016/j.cell.2020.08.053

M3 - Article

C2 - 33064988

AN - SCOPUS:85092455165

SN - 0092-8674

VL - 183

SP - 347-362.e24

JO - Cell

JF - Cell

IS - 2

ER -

A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer

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