An immunogenic personal neoantigen vaccine for patients with melanoma
Patrick A. Ott,Zhuting Hu,Derin B. Keskin,Derin B. Keskin,Sachet A. Shukla,Sachet A. Shukla,Jing Sun,David J. Bozym,Wandi Zhang,Adrienne M. Luoma,Anita Giobbie-Hurder,Lauren Peter,Christina Chen,Oriol Olive,Todd A. Carter,Shuqiang Li,David J. Lieb,Thomas Eisenhaure,Evisa Gjini,Jonathan Stevens,William J. Lane,Indu Javeri,Kaliappanadar Nellaiappan,Andres M. Salazar,Heather Daley,Michael S. Seaman,Elizabeth I. Buchbinder,Elizabeth I. Buchbinder,Charles H. Yoon,Maegan Harden,Niall J. Lennon,Stacey Gabriel,Scott J. Rodig,Scott J. Rodig,Dan H. Barouch,Dan H. Barouch,Dan H. Barouch,Jon C. Aster,Jon C. Aster,Gad Getz,Gad Getz,Kai W. Wucherpfennig,Donna Neuberg,Jerome Ritz,Jerome Ritz,Eric S. Lander,Eric S. Lander,Edward F. Fritsch,Edward F. Fritsch,Nir Hacohen,Nir Hacohen,Catherine J. Wu +51 more
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TLDR
The feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens is demonstrated and a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies is provided.Abstract:
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.read more
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mRNA vaccines — a new era in vaccinology
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Integrative Genomics Viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
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References
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Journal ArticleDOI
Integrative genomics viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: In this article, the authors present an approach for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
A framework for variation discovery and genotyping using next-generation DNA sequencing data
Mark A. DePristo,Eric Banks,Ryan Poplin,Kiran V. Garimella,Jared Maguire,Christopher Hartl,Anthony A. Philippakis,Anthony A. Philippakis,Anthony A. Philippakis,Guillermo del Angel,Manuel A. Rivas,Manuel A. Rivas,Matt Hanna,Aaron McKenna,Timothy Fennell,Andrew Kernytsky,Andrey Sivachenko,Kristian Cibulskis,Stacey Gabriel,David Altshuler,David Altshuler,Mark J. Daly,Mark J. Daly +22 more
TL;DR: A unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs is presented.
Journal ArticleDOI
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Naiyer A. Rizvi,Naiyer A. Rizvi,Matthew D. Hellmann,Matthew D. Hellmann,Alexandra Snyder,Alexandra Snyder,Pia Kvistborg,Vladimir Makarov,Jonathan J. Havel,William Lee,Jianda Yuan,Phillip Wong,Teresa S. Ho,Martin L. Miller,Natasha Rekhtman,Andre L. Moreira,Fawzia Ibrahim,Cameron Bruggeman,Billel Gasmi,Roberta Zappasodi,Yuka Maeda,Chris Sander,Edward B. Garon,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Ton N. Schumacher,Timothy A. Chan,Timothy A. Chan +28 more
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Journal ArticleDOI
Pembrolizumab versus Ipilimumab in Advanced Melanoma
Caroline Robert,Caroline Robert,Caroline Robert,Jacob Schachter,Georgina V. Long,Ana Arance,Jean-Jacques Grob,Laurent Mortier,Laurent Mortier,Adil Daud,Matteo S. Carlino,Catriona M. McNeil,Michal Lotem,James Larkin,Paul Lorigan,Bart Neyns,Christian U. Blank,Omid Hamid,Christine Mateus,Christine Mateus,Ronnie Shapira-Frommer,Ronnie Shapira-Frommer,Michele Kosh,Honghong Zhou,Nageatte Ibrahim,Scot Ebbinghaus,Antoni Ribas +26 more
TL;DR: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.
Journal ArticleDOI
Neoantigens in cancer immunotherapy
TL;DR: Observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.
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