Denis Migliorini1,2, Valérie Dutoit3,4, Mathilde Allard3,4, Nicole Grandjean Hallez1, Eliana Marinari3,4, Valérie Widmer3,4, Géraldine Philippin3,4, Francesca Corlazzoli3,4, Robin Gustave3,4, Mario Kreutzfeldt2, Nathalie Blazek1, Joëlle Wasem1, Andreas Hottinger1, Avinash Koka5, Shahan Momjian5, Alexander Lobrinus2, Doron Merkler, Maria-Isabel Vargas6, Paul R Walker7, Anna Patrikidou1, Pierre-Yves Dietrich1,3,4. 1. Department of Oncology, Clinical Research Unit, Dr Dubois Ferrière Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. 2. Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. 3. Laboratory of Tumor Immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 4. Translational Research Center for Oncohematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. 5. Neurosurgery Division, Department of Neurosciences, Geneva University Hospital, Geneva, Switzerland. 6. Department of Imaging and Medical information Sciences, Neuroradiology Division, Geneva University Hospital, Geneva, Switzerland. 7. Laboratory of Tumor Immunology, Translational Research Center for Oncohematology, Department of Internal Medicine Specialties, University of Geneva, and Division of Oncology, Geneva University Hospitals, Geneva, Switzerland.
Abstract
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 (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen 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 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (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 cluster of differentiation (CD)4 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 T helper 1 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.
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 (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ gliomapatients. 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 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (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 cluster of differentiation (CD)4 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 T helper 1 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 glioblastomapatients. CONCLUSION: We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for gliomapatients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01920191.
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