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Actively personalized vaccination trial for newly diagnosed glioblastoma

Authors :
Marij J. P. Welters
Dominik Maurer
Ulrik Lassen
Martin Löwer
Bernhard Rossler
Ugur Sahin
Andreas von Deimling
Toni Weinschenk
Christian H. Ottensmeier
Elisa Rusch
Colette Song
Valérie Dutoit
Jordi Rodon
Norbert Hilf
Hans Skovgaard Poulsen
Nina Pawlowski
Francisco Martínez-Ricarte
Judith R. Kroep
Juan Sahuquillo
Claudia Wagner
Edward W. Green
Sonja Dorner
Cedrik M. Britten
Franziska Hoffgaard
Jens Fritsche
Ghazaleh Tabatabai
Stefan Stevanovic
Harpreet Singh-Jasuja
Marco Skardelly
Sabrina Kuttruff-Coqui
Hans-Georg Rammensee
Katharina Kiesel
Alexander Ulges
Carsten Reinhardt
Michael Platten
Alexandra Kemmer-Brück
Bracha Shraibman
Denis Migliorini
Sebastian Kreiter
Jordi Piro
Oliver Schoor
Valesca Bukur
Katrin Frenzel
Berta Ponsati
David Capper
Jorg Ludwig
Monika Stieglbauer
Regina Mendrzyk
Miriam Meyer
Sjoerd H. van der Burg
Evelyna Derhovanessian
Pierre-Yves Dietrich
Arie Admon
Arbel D. Tadmor
Manja Idorn
Wolfgang Wick
Hideho Okada
Per thor Straten
Sandra Heesch
Lukas Bunse
Christoph Huber
Katy J. McCann
Cécile Gouttefangeas
John C. Castle
Dutoit Vallotton, Valérie
Migliorini, Denis
Dietrich, Pierre-Yves
Source :
Nature, 565(7738), 240, Nature, Vol. 565, No 7738 (2019) pp. 240-245
Publication Year :
2019

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.

Details

Language :
English
ISSN :
00280836
Database :
OpenAIRE
Journal :
Nature, 565(7738), 240, Nature, Vol. 565, No 7738 (2019) pp. 240-245
Accession number :
edsair.doi.dedup.....11b11cf9d2f3e8456103640b3a57a625