Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

Derin B. Keskin, Annabelle J. Anandappa, Jing Sun, Itay Tirosh, Nathan D. Mathewson, Shuqiang Li, Giacomo Oliveira, Anita Giobbie-Hurder, Kristen Felt, Evisa Gjini, Sachet A. Shukla, Zhuting Hu, Letitia Li, Phuong M. Le, Rosa L. Allesøe, Alyssa R. Richman, Monika S. Kowalczyk, Sara Abdelrahman, Jack E. Geduldig, Sarah Charbonneau, Kristine Pelton, J. Bryan Iorgulescu, Liudmila Elagina, Wandi Zhang, Oriol Olive, Christine McCluskey, Lars R. Olsen, Jonathan Stevens, William J. Lane, Andres M. Salazar, Heather Daley, Patrick Y. Wen, E. Antonio Chiocca, Maegan Harden, Niall J. Lennon, Stacey Gabriel, Gad Getz, Eric S. Lander, Aviv Regev, Jerome Ritz, Donna Neuberg, Scott J. Rodig, Keith L. Ligon, Mario L. Suvà, Kai W. Wucherpfennig, Nir Hacohen, Edward F. Fritsch, Kenneth J. Livak, Patrick A. Ott, Catherine J. Wu and David A. Reardon ()
Additional contact information
Derin B. Keskin: Dana-Farber Cancer Institute
Annabelle J. Anandappa: Dana-Farber Cancer Institute
Jing Sun: Dana-Farber Cancer Institute
Itay Tirosh: Broad Institute of MIT and Harvard
Nathan D. Mathewson: Harvard Medical School
Shuqiang Li: Broad Institute of MIT and Harvard
Giacomo Oliveira: Dana-Farber Cancer Institute
Anita Giobbie-Hurder: Dana-Farber Cancer Institute
Kristen Felt: Center for Immuno-Oncology, Dana-Farber Cancer Institute
Evisa Gjini: Center for Immuno-Oncology, Dana-Farber Cancer Institute
Sachet A. Shukla: Dana-Farber Cancer Institute
Zhuting Hu: Dana-Farber Cancer Institute
Letitia Li: Dana-Farber Cancer Institute
Phuong M. Le: Dana-Farber Cancer Institute
Rosa L. Allesøe: Dana-Farber Cancer Institute
Alyssa R. Richman: Broad Institute of MIT and Harvard
Monika S. Kowalczyk: Broad Institute of MIT and Harvard
Sara Abdelrahman: Center for Immuno-Oncology, Dana-Farber Cancer Institute
Jack E. Geduldig: Dana-Farber Cancer Institute
Sarah Charbonneau: Dana-Farber Cancer Institute
Kristine Pelton: Dana-Farber Cancer Institute
J. Bryan Iorgulescu: Dana-Farber Cancer Institute
Liudmila Elagina: Broad Institute of MIT and Harvard
Wandi Zhang: Dana-Farber Cancer Institute
Oriol Olive: Dana-Farber Cancer Institute
Christine McCluskey: Dana-Farber Cancer Institute
Lars R. Olsen: Technical University of Denmark
Jonathan Stevens: Brigham and Women’s Hospital
William J. Lane: Harvard Medical School
Andres M. Salazar: Oncovir Inc
Heather Daley: Dana-Farber Cancer Institute
Patrick Y. Wen: Dana-Farber Cancer Institute
E. Antonio Chiocca: Harvard Medical School
Maegan Harden: Broad Institute of MIT and Harvard
Niall J. Lennon: Broad Institute of MIT and Harvard
Stacey Gabriel: Broad Institute of MIT and Harvard
Gad Getz: Broad Institute of MIT and Harvard
Eric S. Lander: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Jerome Ritz: Dana-Farber Cancer Institute
Donna Neuberg: Dana-Farber Cancer Institute
Scott J. Rodig: Harvard Medical School
Keith L. Ligon: Broad Institute of MIT and Harvard
Mario L. Suvà: Broad Institute of MIT and Harvard
Kai W. Wucherpfennig: Harvard Medical School
Nir Hacohen: Broad Institute of MIT and Harvard
Edward F. Fritsch: Dana-Farber Cancer Institute
Kenneth J. Livak: Dana-Farber Cancer Institute
Patrick A. Ott: Dana-Farber Cancer Institute
Catherine J. Wu: Dana-Farber Cancer Institute
David A. Reardon: Dana-Farber Cancer Institute

Nature, 2019, vol. 565, issue 7738, 234-239

Abstract: Abstract Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4–6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically ‘cold’ tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone—a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma—generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.

Date: 2019
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DOI: 10.1038/s41586-018-0792-9

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