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, David A Reardon, 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, David A Reardon
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.
Conflict of interest statement
Competing interests: D.A.R. is an advisor to Abbvie, Agenus, Bristol-Myers Squibb, Celldex, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline and Taiho Oncology; he has received research funding support from Acerta Phamaceuticals, Agenus, Celldex, EMD Serono, Incyte, Midatech, Omniox and Tragara. D.B.K. has previously advised Neon Therapeutics and owns equity in Aduro Biotech, Agenus, Ampliphi BioSciences, Biomarin Pharmaceutical, Bristol-Myers Squibb, Celldex Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Sangamo Therapeutics and Stemline Therapeutics. J. Sun is a current employee of Moderna Therapeutics. C.J.W. is a founder of Neon Therapeutics and member of its scientific advisory board. P.A.O. has received research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, AstraZeneca/MedImmune, Armo BioSciences and Roche/Genentech. K.J.L. is a paid consultant for Integrated DNA Technologies. E.F.F. is a founder and employee of Neon Therapeutics. N.H. is a founder of Neon Therapeutics and member of its scientific advisory board and an advisor for IFM therapeutics. K.W.W. is a paid consultant for Novartis, serves on the scientific advisory board for TCR2, Nextech and T-Scan, and receives sponsored research funding from Novartis, BMS and Astellas that is not related to the topic of this manuscript. S.J.R. receives research funding from Bristol-Myers Squibb, Merck, KITE Pharmaceuticals and Affimed Pharmaceuticals, and is on a scientific medical board for Perkin-Elmer. J.R. has consulted for Celgene, Draper Labs and Clarus Ventures. A.R. is a founder of Celsius Therapeutics and a member of the scientific advisory board for ThermoFisher Scientific, Driver Group and Syros Pharmaceuticals. E.S.L. is a founder of Neon Therapeutics and a member of its board of directors. G.G. is receiving research funds from IBM and Pharmacyclics, and is an inventor on patent applications related to MuTect and ABSOLUTE. N.J.L. has advised Neon Therapeutics, is a current advisor of New England Biolabs and is a member of the scientific advisory board for Genturi. E.A.C. is currently an advisor to Advantagene and DNAtrix, and has equity interest in DNATrix; he has previously advised Oncorus, Merck, Tocagen, Ziopharm, StemCell and NanoTx. P.Y.W. has no directly relevant conflicts; he currently sits on advisory boards for Abbvie, AstraZeneca, Eli Lilly, Genentech/Roche, Immunomic Therapeutics, Puma, Vascular Biogenics, Taiho and Deciphera, received speaker fees for Merck and received research support from Agios, AstraZeneca, Beigene, Eli Lilly, Genentech/Roche, Kadmon, Karyopharm, Kazia, Merck, Novartis, Oncoceutics, Sanofi-Aventis and VBI Vaccines. A.M.S. is CEO and CSO of Oncovir. M.S.K. is a current employee of Celsius Therapeutics. S.A.S has previously advised Neon Therapeutics and has equity in 152 Therapeutics. C.J.W. is subject to a conflict of interest management plan for the reported studies because of her competing financial interests in Neon Therapeutics. Under this plan, C.J.W. may not access identifiable data for human subjects or otherwise participate directly in the Institutional Review Board-approved protocol reported herein. C.J.W.’s contributions to the overall strategy and data analyses occurred on a de-identified basis. Patent applications have been filed on aspects of the described work entitled as follows: ‘Compositions and methods for personalized neoplasia vaccines’ (N.H., E.F.F. and C.J.W.), ‘Methods for identifying tumour specific neo-antigens’ (N.H. and C.J.W.), ‘Formulations for neoplasia vaccines’ (E.F.F.) and ‘Combination therapy for neoantigen vaccine’ (N.H., C.J.W. and E.F.F.). The Dana-Farber Cancer Institute, the lead site of this trial, has a proprietary and financial interest in the personalized neoantigen vaccine. As a result of its licensing activities, Dana-Farber Cancer Institute also holds equity in Neon Therapeutics. The remaining authors declare no competing interests.
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Source: PubMed