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

被引：452

作者：

Ott, Patrick A. ^{[1
,2
]}

Hu-Lieskovan, Siwen ^{[3
]}

Chmielowski, Bartosz ^{[3
]}

Govindan, Ramaswamy ^{[4
]}

Naing, Aung ^{[5
]}

Bhardwaj, Nina ^{[6
]}

Margolin, Kim ^{[7
]}

Awad, Mark M. ^{[1
,2
]}

Hellmann, Matthew D. ^{[8
]}

Lin, Jessica J. ^{[2
,9
]}

Friedlander, Terence ^{[10
]}

Bushway, Meghan E. ^{[11
]}

Balogh, Kristen N. ^{[11
]}

Sciuto, Tracey E. ^{[11
]}

Kohler, Victoria ^{[11
]}

Turnbull, Samantha J. ^{[11
]}

Besada, Rana ^{[11
]}

Curran, Riley R. ^{[11
]}

Trapp, Benjamin ^{[11
]}

Scherer, Julian ^{[11
]}

Poran, Asaf ^{[11
]}

Harjanto, Dewi ^{[11
]}

Barthelme, Dominik ^{[11
]}

Ting, Ying Sonia ^{[11
]}

Dong, Jesse Z. ^{[11
]}

Ware, Yvonne ^{[11
]}

Huang, Yuting ^{[11
]}

Huang, Zhengping ^{[11
]}

Wanamaker, Amy ^{[11
]}

Cleary, Lisa D. ^{[11
]}

Moles, Melissa A. ^{[11
]}

Manson, Kelledy ^{[11
]}

Greshock, Joel ^{[11
]}

Khondker, Zakaria S. ^{[11
]}

Fritsch, Ed ^{[11
]}

Rooney, Michael S. ^{[11
]}

DeMario, Mark ^{[11
]}

Gaynor, Richard B. ^{[11
]}

Srinivasan, Lakshmi ^{[11
]}

机构：

[1] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[4] Washington Univ, Sch Med, St Louis, MO USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA

[6] Icahn Sch Med, Tisch Canc Inst, New York, NY USA

[7] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA

[8] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[9] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[10] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA

[11] Neon Therapeut BioNTech US, Cambridge, MA 02139 USA

来源：

CELL | 2020年 / 183卷 / 02期

关键词：

METASTATIC UROTHELIAL CARCINOMA; OPEN-LABEL; CHECKPOINT BLOCKADE; PD-1; BLOCKADE; NIVOLUMAB; IMMUNOTHERAPY; MULTICENTER; GENERATION; RESPONSES; RECEPTOR;

D O I：

10.1016/j.cell.2020.08.053

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase lb clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4(+) and CD8(+) T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors.

引用

页码：347 / +

页数：40

共 77 条

[1] Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction [J].

Abelin, Jennifer G. ;

Harjanto, Dewi ;

Malloy, Matthew ;

Suri, Prerna ;

Colson, Tyler ;

Goulding, Scott P. ;

Creech, Amanda L. ;

Serrano, Lia R. ;

Nasir, Gibran ;

Nasrullah, Yusuf ;

McGann, Christopher D. ;

Velez, Diana ;

Ting, Ying S. ;

Poran, Asaf ;

Rothenberg, Daniel A. ;

Chhangawala, Sagar ;

Rubinsteyn, Alex ;

Hammerbacher, Jeff ;

Gaynor, Richard B. ;

Fritsch, Edward F. ;

Greshock, Joel ;

Oslund, Rob C. ;

Barthelme, Dominik ;

Addona, Terri A. ;

Arleta, Christina M. ;

Rooney, Michael S. .

IMMUNITY, 2019, 51 (04) :766-+

[2] Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction [J].

Abelin, Jennifer G. ;

Keskin, Derin B. ;

Sarkizova, Siranush ;

Hartigan, Christina R. ;

Zhang, Wandi ;

Sidney, John ;

Stevens, Jonathan ;

Lane, William ;

Zhang, Guang Lan ;

Eisenhaure, Thomas M. ;

Clauser, Karl R. ;

Hacohen, Nir ;

Rooney, Michael S. ;

Carr, Steven A. ;

Wu, Catherine J. .

IMMUNITY, 2017, 46 (02) :315-326

[3] MHC-II neoantigens shape tumour immunity and response to immunotherapy [J].

Alspach, Elise ;

Lussier, Danielle M. ;

Miceli, Alexander P. ;

Kizhvatov, Ilya ;

DuPage, Michel ;

Luoma, Adrienne M. ;

Meng, Wei ;

Lichti, Cheryl F. ;

Esaulova, Ekaterina ;

Vomund, Anthony N. ;

Runci, Daniele ;

Ward, Jeffrey P. ;

Gubin, Matthew M. ;

Medrano, Ruan F. V. ;

Arthur, Cora D. ;

White, J. Michael ;

Sheehan, Kathleen C. F. ;

Chen, Alex ;

Wucherpfennig, Kai W. ;

Jacks, Tyler ;

Unanue, Emil R. ;

Artyomov, Maxim N. ;

Schreiber, Robert D. .

NATURE, 2019, 574 (7780) :696-+

[4]

[Anonymous], 2016, Ggplot2: elegant graphics for data analysis

[5]

Aronesty E., 2011, Expr. Anal. Durham

[6] IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade [J].

Ayers, Mark ;

Lunceford, Jared ;

Nebozhyn, Michael ;

Murphy, Erin ;

Loboda, Andrey ;

Kaufman, David R. ;

Albright, Andrew ;

Cheng, Jonathan D. ;

Kang, S. Peter ;

Shankaran, Veena ;

Piha-Paul, Sarina A. ;

Yearley, Jennifer ;

Seiwert, Tanguy Y. ;

Ribas, Antoni ;

McClanahan, Terrill K. .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940

[7] Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial [J].

Balar, Arjun V. ;

Galsky, Matthew D. ;

Rosenberg, Jonathan E. ;

Powles, Thomas ;

Petrylak, Daniel P. ;

Bellmunt, Joaquim ;

Loriot, Yohann ;

Necchi, Andrea ;

Hoffman-Censits, Jean ;

Perez-Gracia, Jose Luis ;

Dawson, Nancy A. ;

van der Heijden, Michiel S. ;

Dreicer, Robert ;

Srinivas, Sandy ;

Retz, Margitta M. ;

Joseph, Richard W. ;

Drakaki, Alexandra ;

Vaishampayan, Ulka N. ;

Sridhar, Srikala S. ;

Quinn, David I. ;

Duran, Ignacio ;

Shaffer, David R. ;

Eigl, Bernhard J. ;

Grivas, Petros D. ;

Yu, Evan Y. ;

Li, Shi ;

Kadel, Edward E., III ;

Boyd, Zachary ;

Bourgon, Richard ;

Hegde, Priti S. ;

Mariathasan, Sanjeev ;

Thastrom, AnnChristine ;

Abidoye, Oyewale O. ;

Fine, Gregg D. ;

Bajorin, Dean F. .

LANCET, 2017, 389 (10064) :67-76

[8] Building and Optimizing a Virus-specific T Cell Receptor Library for Targeted Immunotherapy in Viral Infections [J].

Banu, Nasirah ;

Chia, Adeline ;

Ho, Zi Zong ;

Garcia, Alfonso Tan ;

Paravasivam, Komathi ;

Grotenbreg, Gijsbert M. ;

Bertoletti, Antonio ;

Gehring, Adam J. .

SCIENTIFIC REPORTS, 2014, 4

[9] Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma [J].

Bellmunt, J. ;

de Wit, R. ;

Vaughn, D. J. ;

Fradet, Y. ;

Lee, J. -L. ;

Fong, L. ;

Vogelzang, N. J. ;

Climent, M. A. ;

Petrylak, D. P. ;

Choueiri, T. K. ;

Necchi, A. ;

Gerritsen, W. ;

Gurney, H. ;

Quinn, D. I. ;

Culine, S. ;

Sternberg, C. N. ;

Mai, Y. ;

Poehlein, C. H. ;

Perini, R. F. ;

Bajorin, D. F. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (11) :1015-1026

[10] Sensitive and viable identification of antigen-specific CD8+T cells by a flow cytometric assay for degranulation [J].

Betts, MR ;

Brenchley, JM ;

Price, DA ;

De Rosa, SC ;

Douek, DC ;

Roederer, M ;

Koup, RA .

JOURNAL OF IMMUNOLOGICAL METHODS, 2003, 281 (1-2) :65-78

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