TY - JOUR

T1 - Actively personalized vaccination trial for newly diagnosed glioblastoma

AU - Hilf, Norbert

AU - Kuttruff-Coqui, Sabrina

AU - Frenzel, Katrin

AU - Bukur, Valesca

AU - Stevanović, Stefan

AU - Gouttefangeas, Cécile

AU - Platten, Michael

AU - Tabatabai, Ghazaleh

AU - Dutoit, Valerie

AU - van der Burg, Sjoerd H.

AU - thor Straten, Per

AU - Martínez-Ricarte, Francisco

AU - Ponsati, Berta

AU - Okada, Hideho

AU - Lassen, Ulrik

AU - Admon, Arie

AU - Ottensmeier, Christian H.

AU - Ulges, Alexander

AU - Kreiter, Sebastian

AU - von Deimling, Andreas

AU - Skardelly, Marco

AU - Migliorini, Denis

AU - Kroep, Judith R.

AU - Idorn, Manja

AU - Rodon, Jordi

AU - Piró, Jordi

AU - Poulsen, Hans S.

AU - Shraibman, Bracha

AU - McCann, Katy

AU - Mendrzyk, Regina

AU - Löwer, Martin

AU - Stieglbauer, Monika

AU - Britten, Cedrik M.

AU - Capper, David

AU - Welters, Marij J.P.

AU - Sahuquillo, Juan

AU - Kiesel, Katharina

AU - Derhovanessian, Evelyna

AU - Rusch, Elisa

AU - Bunse, Lukas

AU - Song, Colette

AU - Heesch, Sandra

AU - Wagner, Claudia

AU - Kemmer-Brück, Alexandra

AU - Ludwig, Jörg

AU - Castle, John C.

AU - Schoor, Oliver

AU - Tadmor, Arbel D.

AU - Green, Edward

AU - Fritsche, Jens

AU - Meyer, Miriam

AU - Pawlowski, Nina

AU - Dorner, Sonja

AU - Hoffgaard, Franziska

AU - Rössler, Bernhard

AU - Maurer, Dominik

AU - Weinschenk, Toni

AU - Reinhardt, Carsten

AU - Huber, Christoph

AU - Rammensee, Hans Georg

AU - Singh-Jasuja, Harpreet

AU - Sahin, Ugur

AU - Dietrich, Pierre Yves

AU - Wick, Wolfgang

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.nature.com/articles/s41586-019-0959-z

U2 - 10.1038/s41586-018-0810-y

DO - 10.1038/s41586-018-0810-y

M3 - Letter

C2 - 30568303

AN - SCOPUS:85059762738

VL - 565

SP - 240

EP - 245

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7738

ER -