PMID- 30568303 OWN - NLM STAT- MEDLINE DCOM- 20190507 LR - 20240210 IS - 1476-4687 (Electronic) IS - 0028-0836 (Linking) VI - 565 IP - 7738 DP - 2019 Jan TI - Actively personalized vaccination trial for newly diagnosed glioblastoma. PG - 240-245 LID - 10.1038/s41586-018-0810-y [doi] AB - Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors(1,2). For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential(3). There is limited intratumoural infiltration of immune cells(4) in glioblastoma and these tumours contain only 30-50 non-synonymous mutations(5). 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. FAU - Hilf, Norbert AU - Hilf N AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Kuttruff-Coqui, Sabrina AU - Kuttruff-Coqui S AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Frenzel, Katrin AU - Frenzel K AD - BioNTech AG, Mainz, Germany. FAU - Bukur, Valesca AU - Bukur V AD - BioNTech AG, Mainz, Germany. FAU - Stevanovic, Stefan AU - Stevanovic S AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. FAU - Gouttefangeas, Cecile AU - Gouttefangeas C AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. FAU - Platten, Michael AU - Platten M AD - University Hospital Heidelberg, Heidelberg, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. AD - Medical Faculty Mannheim, Mannheim, Germany. FAU - Tabatabai, Ghazaleh AU - Tabatabai G AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. AD - University Hospital Tubingen, Tubingen, Germany. FAU - Dutoit, Valerie AU - Dutoit V AD - Geneva University Hospital, Geneva, Switzerland. FAU - van der Burg, Sjoerd H AU - van der Burg SH AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. AD - Leiden University Medical Center, Leiden, The Netherlands. FAU - Thor Straten, Per AU - Thor Straten P AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. AD - Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Herlev, Denmark. AD - Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. FAU - Martinez-Ricarte, Francisco AU - Martinez-Ricarte F AD - Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Ponsati, Berta AU - Ponsati B AD - BCN Peptides SA, Barcelona, Spain. FAU - Okada, Hideho AU - Okada H AD - University of California, San Francisco, San Francisco, CA, USA. AD - Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. FAU - Lassen, Ulrik AU - Lassen U AD - Ringhospitalet, Copenhagen, Denmark. FAU - Admon, Arie AU - Admon A AD - Technion - Israel Institute of Technology, Haifa, Israel. FAU - Ottensmeier, Christian H AU - Ottensmeier CH AD - University of Southampton, Southampton, UK. FAU - Ulges, Alexander AU - Ulges A AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Kreiter, Sebastian AU - Kreiter S AD - BioNTech AG, Mainz, Germany. AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. FAU - von Deimling, Andreas AU - von Deimling A AD - University Hospital Heidelberg, Heidelberg, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. FAU - Skardelly, Marco AU - Skardelly M AD - University Hospital Tubingen, Tubingen, Germany. FAU - Migliorini, Denis AU - Migliorini D AD - Geneva University Hospital, Geneva, Switzerland. FAU - Kroep, Judith R AU - Kroep JR AD - Leiden University Medical Center, Leiden, The Netherlands. FAU - Idorn, Manja AU - Idorn M AD - Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Herlev, Denmark. AD - Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. FAU - Rodon, Jordi AU - Rodon J AD - Vall d'Hebron University Hospital, Barcelona, Spain. AD - M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA. FAU - Piro, Jordi AU - Piro J AD - BCN Peptides SA, Barcelona, Spain. FAU - Poulsen, Hans S AU - Poulsen HS AD - Ringhospitalet, Copenhagen, Denmark. FAU - Shraibman, Bracha AU - Shraibman B AD - Technion - Israel Institute of Technology, Haifa, Israel. FAU - McCann, Katy AU - McCann K AD - University of Southampton, Southampton, UK. FAU - Mendrzyk, Regina AU - Mendrzyk R AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Lower, Martin AU - Lower M AD - BioNTech AG, Mainz, Germany. FAU - Stieglbauer, Monika AU - Stieglbauer M AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. FAU - Britten, Cedrik M AU - Britten CM AD - BioNTech AG, Mainz, Germany. AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. AD - Oncology R&D, GlaxoSmithKline, Stevenage, UK. FAU - Capper, David AU - Capper D AD - University Hospital Heidelberg, Heidelberg, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. AD - Charite, University Medicine Berlin, Berlin, Germany. FAU - Welters, Marij J P AU - Welters MJP AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. AD - Leiden University Medical Center, Leiden, The Netherlands. FAU - Sahuquillo, Juan AU - Sahuquillo J AD - Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Kiesel, Katharina AU - Kiesel K AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Derhovanessian, Evelyna AU - Derhovanessian E AD - BioNTech AG, Mainz, Germany. FAU - Rusch, Elisa AU - Rusch E AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. FAU - Bunse, Lukas AU - Bunse L AD - University Hospital Heidelberg, Heidelberg, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. FAU - Song, Colette AU - Song C AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Heesch, Sandra AU - Heesch S AD - BioNTech AG, Mainz, Germany. FAU - Wagner, Claudia AU - Wagner C AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Kemmer-Bruck, Alexandra AU - Kemmer-Bruck A AD - BioNTech AG, Mainz, Germany. FAU - Ludwig, Jorg AU - Ludwig J AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Castle, John C AU - Castle JC AD - BioNTech AG, Mainz, Germany. AD - Agenus Inc., Lexington, KY, USA. FAU - Schoor, Oliver AU - Schoor O AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Tadmor, Arbel D AU - Tadmor AD AD - TRON GmbH - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Mainz, Germany. FAU - Green, Edward AU - Green E AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. AD - Medical Faculty Mannheim, Mannheim, Germany. FAU - Fritsche, Jens AU - Fritsche J AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Meyer, Miriam AU - Meyer M AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Pawlowski, Nina AU - Pawlowski N AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Dorner, Sonja AU - Dorner S AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Hoffgaard, Franziska AU - Hoffgaard F AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Rossler, Bernhard AU - Rossler B AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Maurer, Dominik AU - Maurer D AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Weinschenk, Toni AU - Weinschenk T AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Reinhardt, Carsten AU - Reinhardt C AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Huber, Christoph AU - Huber C AD - BioNTech AG, Mainz, Germany. FAU - Rammensee, Hans-Georg AU - Rammensee HG AD - Eberhard Karls Universitat Tubingen, Tubingen, Germany. AD - German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. FAU - Singh-Jasuja, Harpreet AU - Singh-Jasuja H AD - Immatics Biotechnologies GmbH, Tubingen, Germany. FAU - Sahin, Ugur AU - Sahin U AD - BioNTech AG, Mainz, Germany. FAU - Dietrich, Pierre-Yves AU - Dietrich PY AD - Geneva University Hospital, Geneva, Switzerland. FAU - Wick, Wolfgang AU - Wick W AD - University Hospital Heidelberg, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de. AD - German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de. LA - eng GR - 15951/CRUK_/Cancer Research UK/United Kingdom GR - MR/P024351/1/MRC_/Medical Research Council/United Kingdom PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181219 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Antigens, Neoplasm) RN - 0 (Cancer Vaccines) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-A Antigens) SB - IM CIN - Nature. 2019 Jan;565(7738):170-171. PMID: 30622348 CIN - Nat Rev Neurol. 2019 Feb;15(2):59. PMID: 30643233 CIN - Nat Rev Cancer. 2019 Mar;19(3):129. PMID: 30705432 EIN - Nature. 2019 Feb;566(7745):E13. PMID: 30733620 MH - Adult MH - Aged MH - Antigens, Neoplasm/immunology MH - CD8-Positive T-Lymphocytes/immunology MH - Cancer Vaccines/*immunology/*therapeutic use MH - Epitopes, T-Lymphocyte/immunology MH - Female MH - Glioblastoma/*diagnosis/immunology/*therapy MH - HLA-A Antigens/immunology MH - Humans MH - Immunologic Memory/immunology MH - Male MH - Middle Aged MH - Precision Medicine/*methods MH - T-Lymphocytes, Helper-Inducer/immunology MH - Treatment Outcome EDAT- 2018/12/21 06:00 MHDA- 2019/05/08 06:00 CRDT- 2018/12/21 06:00 PHST- 2018/05/08 00:00 [received] PHST- 2018/11/19 00:00 [accepted] PHST- 2018/12/21 06:00 [pubmed] PHST- 2019/05/08 06:00 [medline] PHST- 2018/12/21 06:00 [entrez] AID - 10.1038/s41586-018-0810-y [pii] AID - 10.1038/s41586-018-0810-y [doi] PST - ppublish SO - Nature. 2019 Jan;565(7738):240-245. doi: 10.1038/s41586-018-0810-y. Epub 2018 Dec 19.