Hilf and Kuttruff-Coqui et al. performed a Phase I trial in 15 newly diagnosed glioblastoma patients of two vaccine compositions (APVAC1 and APVAC2) with poly-ICLC and GM-CSF as adjuvants. In 12 of 13 evaluable patients, APVAC1 (consisting of a personalized selection of 7 pre-manufactured, previously validated, unmutated tumor antigens and 2 pan-DR antigens) increased specific CD8+ and CD4+ T cell responses and shifted tumor-specific CD8+ T cells toward a memory phenotype. In 8 of 10 evaluable patients, APVAC2 (typically consisting of 2 neoepitopes) induced neoepitope-specific CD4+ Th1 T cell responses.

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.

Author Info: (1) Immatics Biotechnologies GmbH, Tubingen, Germany. (2) Immatics Biotechnologies GmbH, Tubingen, Germany. (3) BioNTech AG, Mainz, Germany. (4) BioNTech AG, Mainz, Germany. (5) Eberhard Karls

Author Info: (1) Immatics Biotechnologies GmbH, Tubingen, Germany. (2) Immatics Biotechnologies GmbH, Tubingen, Germany. (3) BioNTech AG, Mainz, Germany. (4) BioNTech AG, Mainz, Germany. (5) Eberhard Karls Universitat Tubingen, Tubingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. (6) Eberhard Karls Universitat Tubingen, Tubingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. (7) University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. Medical Faculty Mannheim, Mannheim, Germany. (8) Eberhard Karls Universitat Tubingen, Tubingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. University Hospital Tubingen, Tubingen, Germany. (9) Geneva University Hospital, Geneva, Switzerland. (10) CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. Leiden University Medical Center, Leiden, The Netherlands. (11) CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Herlev, Denmark. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (12) Vall d'Hebron University Hospital, Barcelona, Spain. (13) BCN Peptides SA, Barcelona, Spain. (14) University of California, San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (15) Ringhospitalet, Copenhagen, Denmark. (16) Technion - Israel Institute of Technology, Haifa, Israel. (17) University of Southampton, Southampton, UK. (18) Immatics Biotechnologies GmbH, Tubingen, Germany. (19) BioNTech AG, Mainz, Germany. CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. (20) University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. (21) University Hospital Tubingen, Tubingen, Germany. (22) Geneva University Hospital, Geneva, Switzerland. (23) Leiden University Medical Center, Leiden, The Netherlands. (24) Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Herlev, Denmark. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (25) Vall d'Hebron University Hospital, Barcelona, Spain. M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA. (26) BCN Peptides SA, Barcelona, Spain. (27) Ringhospitalet, Copenhagen, Denmark. (28) Technion - Israel Institute of Technology, Haifa, Israel. (29) University of Southampton, Southampton, UK. (30) Immatics Biotechnologies GmbH, Tubingen, Germany. (31) BioNTech AG, Mainz, Germany. (32) Eberhard Karls Universitat Tubingen, Tubingen, Germany. CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. (33) BioNTech AG, Mainz, Germany. CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. Oncology R&D, GlaxoSmithKline, Stevenage, UK. (34) University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. Charite, University Medicine Berlin, Berlin, Germany. (35) CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. Leiden University Medical Center, Leiden, The Netherlands. (36) Vall d'Hebron University Hospital, Barcelona, Spain. (37) Immatics Biotechnologies GmbH, Tubingen, Germany. (38) BioNTech AG, Mainz, Germany. (39) Eberhard Karls Universitat Tubingen, Tubingen, Germany. CIMT/CIP - Association for Cancer Immunotherapy, working group Cancer Immunoguiding Program, Mainz, Germany. (40) University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. (41) Immatics Biotechnologies GmbH, Tubingen, Germany. (42) BioNTech AG, Mainz, Germany. (43) Immatics Biotechnologies GmbH, Tubingen, Germany. (44) BioNTech AG, Mainz, Germany. (45) Immatics Biotechnologies GmbH, Tubingen, Germany. (46) BioNTech AG, Mainz, Germany. Agenus Inc., Lexington, KY, USA. (47) Immatics Biotechnologies GmbH, Tubingen, Germany. (48) TRON GmbH - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Mainz, Germany. (49) German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. Medical Faculty Mannheim, Mannheim, Germany. (50) Immatics Biotechnologies GmbH, Tubingen, Germany. (51) Immatics Biotechnologies GmbH, Tubingen, Germany. (52) Immatics Biotechnologies GmbH, Tubingen, Germany. (53) Immatics Biotechnologies GmbH, Tubingen, Germany. (54) Immatics Biotechnologies GmbH, Tubingen, Germany. (55) Immatics Biotechnologies GmbH, Tubingen, Germany. (56) Immatics Biotechnologies GmbH, Tubingen, Germany. (57) Immatics Biotechnologies GmbH, Tubingen, Germany. (58) Immatics Biotechnologies GmbH, Tubingen, Germany. (59) BioNTech AG, Mainz, Germany. (60) Eberhard Karls Universitat Tubingen, Tubingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center Partner Site Tubingen, Tubingen, Germany. (61) Immatics Biotechnologies GmbH, Tubingen, Germany. (62) BioNTech AG, Mainz, Germany. (63) Geneva University Hospital, Geneva, Switzerland. (64) University Hospital Heidelberg, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de.

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