Actively personalized vaccination trial for newly diagnosed glioblastoma

• Published in: Nature (London) Vol. 565; no. 7738; pp. 240 - 245
• Main Authors: 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, Wick, Wolfgang
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2019
• Subjects: Adjuvants; Adult; Aged; Amino acids; Analysis; Antigens; Antigens, Neoplasm - immunology; Brain cancer; Cancer therapies; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Carboxymethylcellulose; CD4 antigen; CD4 lymphocytes; CD8 antigen; CD8 lymphocytes; CD8-Positive T-Lymphocytes - immunology; Colony-stimulating factor; Consortia; Customization; Diagnosis; Dosage and administration; Drug therapy; Epitopes, T-Lymphocyte - immunology; Exploitation; Female; Flow cytometry; Glioblastoma; Glioblastoma - diagnosis; Glioblastoma - immunology; Glioblastoma - therapy; Glioblastomas; Glioma; Good Manufacturing Practice; Granulocyte-macrophage colony stimulating factor; Granulocytes; Hepatitis; Histocompatibility antigen HLA; HLA-A Antigens - immunology; Humans; Immune checkpoint; Immunogenicity; Immunologic Memory - immunology; Immunological memory; Immunotherapy; Infiltration; Leukocytes; Ligands; Lymphocytes; Lymphocytes T; Lysine; Male; Mass spectrometry; Melanoma; Memory cells; Metastases; Methods; Middle Aged; Mutation; Patients; Peptides; Poly-L-lysine; Precision medicine; Precision Medicine - methods; Scientific imaging; T-Lymphocytes, Helper-Inducer - immunology; Testing; Treatment Outcome; Tumors; Vaccination; Vaccines; Viral infections; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0810-y

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors . For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential . There is limited intratumoural infiltration of immune cells in glioblastoma and these tumours contain only 30-50 non-synonymous mutations . 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.