Hanna Meister - Academia.edu (original) (raw)

Papers by Hanna Meister

Neuro-oncology, Nov 1, 2019

DNP, Jul 29, 2019

Maligne Gliome weisen trotz multimodaler Therapie eine schlechte Prognose auf. Innovative immunth... more Maligne Gliome weisen trotz multimodaler Therapie eine schlechte Prognose auf. Innovative immuntherapeutische Verfahren haben die Behandlungsmöglichkeiten zahlreicher Tumore entscheidend verbessert und bieten auch für die Neuroonkologie neue Therapieansätze, die in diesem Artikel dargestellt werden. Einführung Gliome sind die häu gsten hirneigenen Tumore im Erwachsenenalter. In etwa der Häl e der Fälle liegt bei Erstdiagnose ein hochmalignes Glioblastom (GBM) vor [1], das trotz der multimodalen Standardtherapie, bestehend aus Resektion, Bestrahlung und Chemotherapie, ein medianes Gesamtüberleben von etwa ein bis eineinhalb Jahren aufweist [2]. Der dringende Bedarf an neuen, wirksamen erapien ist daher o ensichtlich. Verschiedene immunologische erapiekonzepte haben bei Tumoren wie dem malignen Melanom, dem nicht kleinzelligen Bronchialkarzinom und bestimmten Leukämien zu bemerkenswerten Erfolgen geführt und Eingang in die klinische Praxis gefunden. Diese bieten auch für die Neuroonkologie attraktive Ansätze. Zu den wichtigsten Konzepten gehören Vakzinierungen, der Einsatz von Immuncheckpoint-In-hibitoren sowie der adoptive Zelltransfer genetisch modizierter Immunzellen. Dabei wird die erapie zunehmend auf der Grundlage molekulargenetischer Analysen des Tumormaterials individualisiert. Hier geben wir einen Überblick über die grundlegenden Prinzipien verschiedener immunologischer Behandlungsstrategien, diskutieren ihre Besonderheiten im Kontext von Gliomen und fassen erste Erkenntnisse zur Durchführbarkeit, Sicherheit und Wirksamkeit bei malignen Gliomen zusammen. Besonderheiten des ZNS Aufgrund ihrer Lokalisation im ZNS sowie gewisser tumorbiologischer Eigenscha en von Gliomen sind bei der Übertragung bestehender erapieansätze auf Gliome einige Besonderheiten zu beachten. Die Blut-Hirn-Schranke (BHS) ist für die

Clinical Cancer Research, Aug 29, 2022

Supplementary Data from Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activi... more Supplementary Data from Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity Against Glioblastoma

Neuro-oncology, Aug 1, 2019

BACKGROUND: Cancer immunotherapy with genetically engineered T cells that express a chimeric anti... more BACKGROUND: Cancer immunotherapy with genetically engineered T cells that express a chimeric antigen receptor (CAR) has led to impressive responses in extracranial malignancies and is also explored against glioblastoma. However, CAR T cell strategies that are currently being explored against glioblastoma target single tumor antigens, which are non-homogeneously expressed and are prone to antigen escape. Furthermore, the immunosuppressive brain tumor microenvironment hampers anti-tumor efficacy. METHODS: By immunohistochemistry and flow cytometry, we investigated the expression of CD155 and CD112, which are ligands to the activating immune cell receptor DNAX accessory molecule-1 (DNAM-1), in human and mouse glioma cell lines as well as in human glioblastoma samples. To understand their functional role, we generated CD155 or CD112 knockout glioma cell lines using CRISPR/Cas9 and studied proliferation, sensitivity to irradiation or temozolomide as well as migration. To exploit the promiscuous binding features of DNAM-1, we generated different first or second-generation CAR T cells that use DNAM-1 as a tumor-binding domain. Subsequently, we investigated their anti-tumor activity in vitro in co-culture assays and in vivo in syngeneic orthotopic murine glioma models. RESULTS: CD155 and CD112 are homogenously expressed in human and mouse glioma cell lines and human glioblastoma tissues. Knockout of these ligands affected the migration of tumor cells, but did not affect proliferation or sensitivity to irradition or temozolomide. DNAM-1-based CAR T cells demonstrated high cytolytic activity and effector cytokine secretion in vitro. In vivo, DNAM-1 based CAR T cells reached to the tumor site in the brain upon intravenous administration, prolonged survival of orthotopic glioma-bearing mice and led to a durable anti-tumor response in a fraction of mice. The treatment was tolerated without toxicities. CONCLUSION: We elucidated the tumorintrinisic role of CD155 and CD112 and provide the first systematical preclincal assessment of DNAM-1 CAR T cells against glioma. These findings provide a rationale to test this immunotherapeutic strategy also in human glioma patients.

Supplementary Figure from Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Acti... more Supplementary Figure from Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity Against Glioblastoma

Purpose:Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstr... more Purpose:Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma.Experimental Design:We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo.Results:Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without s...

Clinical Cancer Research

Purpose: Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonst... more Purpose: Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma. Experimental Design: We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo. Results: Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models with...

Cell Reports, 2020

Despite successful clot retrieval in large vessel occlusion stroke, 50% of patients have an unfav... more Despite successful clot retrieval in large vessel occlusion stroke, 50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of 20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke.

Neuro-Oncology, 2019

BACKGROUND Genetically engineered T cells that express a chimeric antigen receptor (CAR) have sho... more BACKGROUND Genetically engineered T cells that express a chimeric antigen receptor (CAR) have shown powerful anti-tumor activity in extracranial malignancies. This concept is now also being explored against glioblastoma. However, many single target antigens used for CAR cell therapy are non-homogeneously expressed. We assessed the therapeutic potential of CAR T cells targeting 2 antigens which are homogeneously expressed by glioma cells which reduces the probability of tumor immune escape due to antigen loss. METHODS We analyzed the expression of CD112 and CD155, which are ligands to the activating immune cell receptor DNAX Accessory Molecule-1 (DNAM-1), in a panel of mouse and human glioma cell lines as well as in human glioblastoma samples and generated glioma cells with a CD112 or CD155 knock-out. To exploit the specific binding properties of DNAM-1, we generated first or second-generation CAR T cells that use DNAM-1 as an antigen-binding domain and investigated their anti-tumor ...

DNP - Der Neurologe & Psychiater, 2019