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Actively personalized vaccination trial for newly diagnosed glioblastoma

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

Original languageEnglish
JournalNature
Volume565
Issue number7738
Pages (from-to)240-245
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - 10 Jan 2019

ID: 56272044