Migliorini and Dutoit et al. immunized 19 glioma patients with 9 HLA-A2 epitope-length peptides (identified from glioblastoma tumor samples using mass spectrometry and shown to be overexpressed in gliomas and immunogenic in vitro) and 2 HLA-DR peptides. The initial 6 patients received the peptides intradermally and poly-ICLC intramuscularly, and showed few T cell responses. Combining peptide and adjuvant improved immunogenicity, particularly evidenced by induction of multiple CD8+ and CD4+ T cell responses per patient. Clinical outcomes were unremarkable for this small cohort and there were no signs of immunoediting.
Background: Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC in HLA-A2 + glioma patients. Methods: Adult patients with newly diagnosed glioblastoma (n=16) and grade III astrocytoma (n=3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 MHC class I and 2 MHC class II peptides) i.d. and poly-ICLC i.m. After protocol amendment, IMA950 and poly-ICLC were mixed and injected s.c. (n=7) or i.m. (n=6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral CD4 and CD8 T cell responses. Results: The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained Th1 CD4 T cell responses. For the entire cohort, CD8 T cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients. Conclusion: We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients. Trial registration: Clinicaltrials.gov NCT01920191.
Author Info: (1) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (2) Laboratory of Tumor im
Author Info: (1) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (2) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (3) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (4) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (5) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (6) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (7) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (8) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (9) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (10) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (11) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (12) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (13) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (14) Neurosurgery Division, Department of Neurosciences, Geneva University Hospital, Geneva, Switzerland. (15) Neurosurgery Division, Department of Neurosciences, Geneva University Hospital, Geneva, Switzerland. (16) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (17) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (18) Department of Imaging and Medical information Sciences, Neuroradiology Division, Geneva University Hospital, Geneva, Switzerland. (19) Laboratory of Tumor immunology, Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, & Division of Oncology, HUG, Geneva, Switzerland. (20) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (21) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland.
