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Actively personalized vaccination trial for newly diagnosed glioblastoma

Actively personalized vaccination trial for newly diagnosed glioblastoma
Actively personalized vaccination trial for newly diagnosed glioblastoma

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

0028-0836
240-245
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Singh-Jasuja, Harpreet
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Sahin, Ugur
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Wick, Wolfgang
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Hilf, Norbert
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Kuttruff-Coqui, Sabrina
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Frenzel, Katrin
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Bukur, Valesca
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Stevanović, Stefan
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Gouttefangeas, Cécile
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Platten, Michael
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Tabatabai, Ghazaleh
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Dutoit, Valerie
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van der Burg, Sjoerd H.
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thor Straten, Per
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Ponsati, Berta
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Lassen, Ulrik
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McCann, Katy
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Pawlowski, Nina
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Hilf, Norbert, Kuttruff-Coqui, Sabrina, Frenzel, Katrin, Bukur, Valesca, Stevanović, Stefan, Gouttefangeas, Cécile, Platten, Michael, Tabatabai, Ghazaleh, Dutoit, Valerie, van der Burg, Sjoerd H., thor Straten, Per, Martínez-Ricarte, Francisco, Ponsati, Berta, Okada, Hideho, Lassen, Ulrik, Admon, Arie, Ottensmeier, Christian H., Ulges, Alexander, Kreiter, Sebastian, von Deimling, Andreas, Skardelly, Marco, Migliorini, Denis, Kroep, Judith R., Idorn, Manja, Rodon, Jordi, Piró, Jordi, Poulsen, Hans S., Shraibman, Bracha, McCann, Katy, Mendrzyk, Regina, Löwer, Martin, Stieglbauer, Monika, Britten, Cedrik M., Capper, David, Welters, Marij J.P., Sahuquillo, Juan, Kiesel, Katharina, Derhovanessian, Evelyna, Rusch, Elisa, Bunse, Lukas, Song, Colette, Heesch, Sandra, Wagner, Claudia, Kemmer-Brück, Alexandra, Ludwig, Jörg, Castle, John C., Schoor, Oliver, Tadmor, Arbel D., Green, Edward, Fritsche, Jens, Meyer, Miriam, Pawlowski, Nina, Dorner, Sonja, Hoffgaard, Franziska, Rössler, Bernhard, Maurer, Dominik, Weinschenk, Toni, Reinhardt, Carsten, Huber, Christoph, Rammensee, Hans Georg, Singh-Jasuja, Harpreet, Sahin, Ugur, Dietrich, Pierre Yves and Wick, Wolfgang (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature, 565 (7738), 240-245. (doi:10.1038/s41586-018-0810-y).

Record type: Letter

Abstract

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

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Accepted/In Press date: 19 November 2018
e-pub ahead of print date: 19 December 2018
Published date: 10 January 2019

Identifiers

Local EPrints ID: 427865
URI: https://eprints.soton.ac.uk/id/eprint/427865
ISSN: 0028-0836
PURE UUID: d18f3ff5-af56-4d7f-9524-e064c3247b16

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Date deposited: 30 Jan 2019 17:30
Last modified: 15 Aug 2019 04:01

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Contributors

Author: Norbert Hilf
Author: Sabrina Kuttruff-Coqui
Author: Katrin Frenzel
Author: Valesca Bukur
Author: Stefan Stevanović
Author: Cécile Gouttefangeas
Author: Michael Platten
Author: Ghazaleh Tabatabai
Author: Valerie Dutoit
Author: Sjoerd H. van der Burg
Author: Per thor Straten
Author: Francisco Martínez-Ricarte
Author: Berta Ponsati
Author: Hideho Okada
Author: Ulrik Lassen
Author: Arie Admon
Author: Alexander Ulges
Author: Sebastian Kreiter
Author: Andreas von Deimling
Author: Marco Skardelly
Author: Denis Migliorini
Author: Judith R. Kroep
Author: Manja Idorn
Author: Jordi Rodon
Author: Jordi Piró
Author: Hans S. Poulsen
Author: Bracha Shraibman
Author: Katy McCann
Author: Regina Mendrzyk
Author: Martin Löwer
Author: Monika Stieglbauer
Author: Cedrik M. Britten
Author: David Capper
Author: Marij J.P. Welters
Author: Juan Sahuquillo
Author: Katharina Kiesel
Author: Evelyna Derhovanessian
Author: Elisa Rusch
Author: Lukas Bunse
Author: Colette Song
Author: Sandra Heesch
Author: Claudia Wagner
Author: Alexandra Kemmer-Brück
Author: Jörg Ludwig
Author: John C. Castle
Author: Oliver Schoor
Author: Arbel D. Tadmor
Author: Edward Green
Author: Jens Fritsche
Author: Miriam Meyer
Author: Nina Pawlowski
Author: Sonja Dorner
Author: Franziska Hoffgaard
Author: Bernhard Rössler
Author: Dominik Maurer
Author: Toni Weinschenk
Author: Carsten Reinhardt
Author: Christoph Huber
Author: Hans Georg Rammensee
Author: Harpreet Singh-Jasuja
Author: Ugur Sahin
Author: Pierre Yves Dietrich
Author: Wolfgang Wick

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