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Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma.sup.1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II.sup.4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H).sup.+ tumours in syngeneic MHC-humanized mice.sup.4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H).sup.+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG.sup.+ and CXCL13.sup.+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor. A phase 1 clinical trial provides evidence that a vaccine against mutant IDH1 is safe and produces a T helper immune response in patients with glioma., Author(s): Michael Platten [sup.1] [sup.2] [sup.3] , Lukas Bunse [sup.1] [sup.2] , Antje Wick [sup.4] [sup.5] , Theresa Bunse [sup.1] [sup.2] , Lucian Le Cornet [sup.6] , Inga Harting [sup.7] [...]

Glioblastoma is the most common malignant primary brain tumor with poor overall survival. Magnetic resonance imaging (MRI) is the main imaging modality for glioblastoma but has inherent shortcomings. The molecular and cellular basis of MR signals is incompletely understood. We established a ground truth-based image analysis platform to coregister MRI and light sheet microscopy (LSM) data to each other and to an anatomic reference atlas for quantification of 20 predefined anatomic subregions. Our pipeline also includes a segmentation and quantification approach for single myeloid cells in entire LSM datasets. This method was applied to three preclinical glioma models in male and female mice (GL261, U87MG, and S24), which exhibit different key features of the human glioma. Multiparametric MR data including T2-weighted sequences, diffusion tensor imaging, T2 and T2* relaxometry were acquired. Following tissue clearing, LSM focused on the analysis of tumor cell density, microvasculature, and innate immune cell infiltration. Correlated analysis revealed differences in quantitative MRI metrics between the tumor-bearing and the contralateral hemisphere. LSM identified tumor subregions that differed in their MRI characteristics, indicating tumor heterogeneity. Interestingly, MRI signatures, defined as unique combinations of different MRI parameters, differed greatly between the models. The direct correlation of MRI and LSM allows an in-depth characterization of preclinical glioma and can be used to decipher the structural, cellular, and, likely, molecular basis of tumoral MRI biomarkers. Our approach may be applied in other preclinical brain tumor or neurologic disease models, and the derived MRI signatures could ultimately inform image interpretation in a clinical setting. [ABSTRACT FROM AUTHOR]

Gliomas are highly treatment refractory against immune checkpoint blockade, an immunotherapeutic modality that revolutionized therapy for many tumors. At the same time, technological innovation has dramatically accelerated the development of immunotherapeutic approaches such as personalized tumor-specific vaccine production, dendritic cell vaccine manufacture, patient-individual target selection and chimeric antigen receptor, and T cell receptor T cell manufacture. Here we review recent clinical and translational advances in glioma immunotherapy with a focus on targets and their cognate immune receptor derivates as well as concepts to improve intratumoral T cell effector functions. [ABSTRACT FROM AUTHOR]

Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design. [ABSTRACT FROM AUTHOR]

Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations. [ABSTRACT FROM AUTHOR]

Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model. By proving an immunologically effective presentation of the driver mutation H3K27M on MHC class II in human H3K27M-mutant gliomas, our data provide a basis for the further clinical development of vaccine-based or cell-based immunotherapeutic approaches targeting H3K27M. [ABSTRACT FROM PUBLISHER]