Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma
. 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
. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)
tumours in syngeneic MHC-humanized mice
. 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)
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
and CXCL13
T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual ...resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and T
expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors
. For treatments using checkpoint inhibitors to be ...successful, a high mutational load and responses to neoepitopes are thought to be essential
. There is limited intratumoural infiltration of immune cells
in glioblastoma and these tumours contain only 30-50 non-synonymous mutations
. 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.
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.
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.
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in ...astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
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•Energy policy increasingly requires an consumption-based accounting (CBA) approach.•But multi-regional input-output (MRIO) models lack robust input energy vectors.•In response we ...complete the first empirical MRIO analysis testing 2 energy vectors.•Energy-use and energy-extracted vectors give insight to different policy questions.•MRIO models should provide both vectors to encourage consistent CBA energy analysis.
Increasing attention has been focussed on the use of consumption-based approaches to energy accounting via input-output (IO) methods. Of particular interest is the examination of energy supply chains, given the associated risks from supply-chain issues, including availability shocks, taxes on fossil fuels and fluctuating energy prices. Using a multiregional IO (MRIO) database to calculate energy consumption-based accounts (CBA) allows analysts to both determine the quantity and source of energy embodied in products along the supply chain. However, it is recognised in the literature that there is uncertainty as to the most appropriate type of energy data that should be employed in an IO framework. Questions arise as to whether an energy extension vector should show where the energy was extracted or where it was used (burnt). In order to address this gap, we undertake the first empirical MRIO analysis of an energy CBA using both vectors. Our results show that both the energy-extracted and energy-used vectors produce similar estimates of the overall energy CBA for the UK—notably 45% higher than territorial energy requirements. However, at a more granular level, the results show that the type of vector that should be employed ultimately depends on the research question that is considered. For example, the energy-extracted vector reveals that just 20% of the UK’s energy CBA includes energy extracted within the UK, an issue that is upmost importance for energy security policy. At the other end, the energy-used vector allows for the attribution of actual energy use to industry sectors, thereby enabling a better understanding of sectoral efficiency gains. These findings are crucial for users and developers of MRIO databases who undertake energy CBA calculations. Since both vectors appear useful for different energy questions, the construction of robust and consistent energy-used and energy-extracted extension vectors as part of commonly-used MRIO model databases is encouraged.
•Empirical analysis identifies a typology of seven knowledge exchange evaluations.•There are five main principles of evaluating knowledge exchange in environmental change research.•Understanding ...underlying processes is important for understanding the role of knowledge exchange in shaping outcomes.
Interdisciplinary and multi-stakeholder research is increasingly being promoted and implemented to enhance understanding of global environment change, identify holistic policy solutions, and assist implementation. These research activities are social processes aiming to enhance the exchange and translation of knowledge. Emphasis on the design and management of knowledge exchange is increasing, but learning about how to do this better is hampered by lack of conceptual development and appropriate methods to evaluate complex and multifaceted knowledge exchange processes. This paper therefore develops principles for the evaluation of knowledge exchange in interdisciplinary, multi-stakeholder environmental change research. The paper is based on an analysis of 135 peer-reviewed evaluations of knowledge exchange from diverse disciplines. The results indicate strong relationships between the field of study (e.g. health care, environmental management), the way knowledge and knowledge exchange were conceptualised and implemented, the approach used for the evaluation, and the outcomes being evaluated. A typology of seven knowledge exchange evaluations is presented to guide discussions about the underlying assumptions of different approaches to knowledge exchange and its evaluation. Five principles for knowledge exchange evaluation are also identified: (i) design for multiple end users; (ii) be explicit about why a particular approach to knowledge exchange is expected to deliver its outcomes; (iii) evaluate diverse outcomes; (iv) use evaluations as part of the process of delivering knowledge exchange; and (v) use mixed methods to evaluate knowledge exchange. We conclude that a catch-all approach to evaluation is neither appropriate nor desirable. Instead, approaches that focus on understanding the underlying processes of knowledge exchange, assess the relative contribution of other factors in shaping outcomes in addition to knowledge exchange, and that involve multiple stakeholders in implementing evaluations, will be the most appropriate for evaluating knowledge exchange in interdisciplinary global environmental change research.
The present review introduces recent progress in eliciting the role of mutant isocitrate dehydrogenase (IDH) in gliomas, especially regarding its mode of action as a modulator of antitumor immune ...response, and provides rationales for targeting mutant IDH in glioma immunotherapy. Both the development of small molecule inhibitors repressing the enzymatic activity of mutant IDH and novel, mechanism-led combination immunotherapies are discussed.
Since the discovery of highly frequent IDH mutations in low-grade gliomas and nonsolid malignancies, its tumor cell-intrinsic effects have been intensively investigated. Tumor cells expressing mutant IDH display profound alterations of redox control capacity, phospholipid profile, and ATP supply. Recent findings suggest that IDH mutations - via intricate, yet druggable pathways - cause immunological alterations, highlighting the importance of oncogenic drivers as modulators of antitumor immunity and targets for immunotherapy.
Mutant IDH is not only a disease-defining biomarker and oncogenic driver in glioma, but is also a neoantigen and a regulator of glioma immune evasion. Effective and specific strategies targeting the immunomodulatory properties of mutant IDH may complement current (immuno-)therapeutic strategies and approved antiglioma treatments to improve outcome.
The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and ...demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
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