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|Authors||Michael Platten, Daniela Schilling, Lukas Bunse, Antje Wick, Theresa Bunse, Dennis Riehl, Irini Karapanagiotou-Schenkel, Inga Harting, Felix Sahm, Anita Schmitt, Joachim Peter Steinbach, Astrid Weyerbrock, Jörg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Andreas von Deimling, Michael Schmitt, Wolfgang Wick|
|Title||A mutation-specific peptide vaccine targeting IDH1R132H in patients with newly diagnosed malignant astrocytomas: A first-in-man multicenter phase I clinical trial of the German Neurooncology Working Group (NOA-16)|
|Journal||Journal of Clinical Oncology|
|Date||May 20, 2018|
|Abstract Text||Background: Hot-spot point mutations in the gene for isocitrate dehydrogenase type 1 (IDH1R132H) are a frequent founder event in gliomas and other tumors. Preclinical studies have defined IDH1R132H as a clonal neoantigen presented on MHC class II to induce tumor-specific therapeutic T helper cell responses. Methods: NOA-16 (NCT02454634) is a first-in-man, multicenter, phase I trial, which enrolled 33 patients with newly diagnosed WHO °III and °IV astrocytomas with IDH1R132H mutations. After completion of radiochemotherapy a total of eight vaccinations with an IDH1R132H peptide in incomplete Freund’s adjuvant produced at a central GMP site was to be administered subcutaneously with topical imiquimod over a period of 32 weeks together with maintenance temozolomide. The primary end points were safety and immunogenicity. Results: The safety dataset comprised 249 vaccines administered to 32 patients. One patient withdrew after screening. 29 patients received all eight vaccines. Vaccine-related adverse events (AE) were restricted to grade 1 reactions, according to common toxicity criteria for AE(CTCAE v4.0). Two serious AE were observed in two patients; one probably related to the peptide vaccine. 28/30 patients (93.3%) evaluable for immunogenicity displayed IDH1R132H-specific T cellular (detected by ELISPOT assays in 24/30 (80%)) or humoral (detected by ELISA in 26/30 patients (87%)) immune responses not detectable before vaccination. Until end of study (EOS, week 32), 4/32 (12.5 %) patients had progressive disease (PD) according to RANO criteria, all other patients (N = 28, 87.5%) had stable disease (SD). 12/32 (37.5%) patients displayed pseudoprogressions. Single-cell T cell receptor (TCR) sequencing allowed for the identification of IDH1R132H-specific TCRs. Conclusions: NOA-16 met its primary endpoints by demonstrating safety and immunogenicity of a mutation-specific IDH1R132H peptide vaccine. Pseudoprogressions observed after the initiation of the vaccine may indicate intratumoral immune reactions warranting further development, including TCR cell therapy. Clinical trial information: NCT02454634.|
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|IDH1 R132H||malignant astrocytoma||predicted - sensitive||IDH1 R132H peptide vaccine||Phase I||Actionable||In a Phase I trial (NOA-16), treatment with IDH1 R132H peptide vaccine demonstrated safety in patients with malignant astrocytoma harboring IDH1 R132H and led to stable disease in 87.5% (28/32) of patients (J Clin Oncol 36, no. 15_suppl (May 20, 2018) 2001; NCT02454634).||detail...|