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  • 1
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    Toxicities and Response Rates of Secondary CNS Lymphoma After Adoptive Immunotherapy With CD19-Directed Chimeric Antigen Receptor T Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Vol. 98, No. 21 ( 2022-05-24), p. 884-889
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 98, No. 21 ( 2022-05-24), p. 884-889
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000200608
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 2
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    BSCI-08. In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Advances Vol. 3, No. Supplement_3 ( 2021-08-09), p. iii2-iii3
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 3, No. Supplement_3 ( 2021-08-09), p. iii2-iii3
    Abstract: Brain metastases represent a common complication of lung cancer and dramatically limit prognosis in affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized, but might be of therapeutic relevance. Methods We established an orthotopic cerebral metastasis model using CX3CR1-proficient (CX3CR1GFP/wt) and -deficient (CX3CR1GFP/GFP) mice with green-fluorescent TAM/M. A cranial window was prepared, and intracarotid injection of red-fluorescent Lewis Lung Carcinoma-cells (tdtLLC) was performed two weeks later. Formation of brain metastases was followed by repetitive two-photon laser scanning microscopy. Results After intracarotid injection, intravascular tumor cells extravasated into the cerebral parenchyma and eventually formed micrometastases (≤50 cells) and mature macrometastases ( & gt;50 cells). We observed phagocytosis of extravasated tumor cells by TAM/M during early steps of metastatic growth. Notably, these anti-tumor effects of TAM/M diminished during later steps of metastasis formation and were accompanied by TAM/M accumulation and activation. CX3CR1-deficiency resulted in a lower number of extravasated tumor cells, and only a small number of TAM/M were visualized during early steps of metastasis formation (extravasation, formation of micrometastases) in such mice. In contrast, progression of extravasated tumor cells into micrometastases was more frequently found in CX3CR1-deficient mice. Overall, these mechanisms resulted in a comparable number of mature macrometastases between CX3CR1-deficient and -proficient mice. Conclusion Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic approach to prevent cerebral dissemination of lung cancer cells. Given the close interaction between TAM/M and tumour cells during metastasis formation, other therapeutic approaches targeting TAM/M function warrant evaluation. Such concepts might be evaluated in vivo using the herein established orthotopic mouse model.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdab071.007
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 3
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    TAMI-02. DEPLETION OF INTRATUMORAL TUMOR-ASSOCIATED MACROPHAGES AND MICROGLIA (TAM/M) IMPROVES CHECKPOINT-INHIBITION THERAPY FOR BRAIN METASTASIS FROM LUNG CANCER
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi198-vi198
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi198-vi198
    Abstract: Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors. METHODS Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1GFP/wt-mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks. RESULTS Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm2 (PD1-inhibition only) versus 0.9 mm2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm2 (PD1-inhibition + small molecular CSF1R-inhibitor)) (p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody. CONCLUSION Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.786
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 4
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    In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
    Informa UK Limited ; 2023
    In:  OncoImmunology Vol. 12, No. 1 ( 2023-12-31)
    Details
    In: OncoImmunology, Informa UK Limited, Vol. 12, No. 1 ( 2023-12-31)
    Type of Medium: Online Resource
    ISSN: 2162-402X
    URL: Article
    DOI: 10.1080/2162402X.2022.2163781
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2023
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  • 5
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    NIMG-51. 18KDA TRANSLOCATOR PROTEIN (TSPO) DECLINES IN TUMOR AND IMMUNE CELLS DURING PROGRESSION OF EXPERIMENTAL GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii175-vii175
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii175-vii175
    Abstract: Glioblastoma combines a lack of immunogenicity with a highly immunosuppressive tumor microenvironment (TME), including both tumor and immune cells. However, biomarkers that allow monitoring of the immune phenotype are still lacking. Hence, we investigated the 18kDa translocator protein (TSPO) during tumor progression in an experiential glioblastoma mouse model (SB28) mimicking human TME. We used TSPO-PET imaging ([18F]GE-180) and in vivo measures of single cell tracer uptake between days 6 and 18 after inoculation to study alterations and dependence of TSPO in tumor and peripheral organs in SB28 mice (n= 27) in comparison to sham controls (n= 11). CSF1R inhibition was applied to deplete tumor associated microglia/macrophages (TAM) followed by withdrawal to induce immune cell rebound (PLX5622 day -20 to day 6, n= 3). Compared to sham, TSPO-PET signals were distinctly elevated in tumor (+83%, p & lt; 0.001), heart (+35%, p & lt; 0.05), lung (+42%, p & lt; 0.01) and bone (+26%, p & lt; 0.05) of SB28 mice at day 6. TSPO-PET increases were lower at day 18 (tumor: +52%, p & lt; 0.05; all organs & lt; +15%, n.s.). The tumor TSPO-PET signal was strongly coupled with TSPO-PET signal in peripheral organs (all R≥ 0.88, all p & lt; 0.001). Single tumor cells and TAM showed strong early increases of TSPO tracer uptake at day 6 (tumor: 32-fold, TAM: 8.5-fold) and a decline of these increases at day 18 (tumor: 2.4-fold, TAM: 1.7-fold) when compared to sham microglia. Immune cell rebound restored TSPO tracer uptake in TAM (+120%, p & lt; 0.01) but not in tumor cells (-24%, n.s.) when compared to therapy-naïve SB28 mice. TSPO declines in tumor cells and TAM during progression of experimental glioblastoma. TSPO in peripheral organs could serve as a supportive indicator of declining immune response in glioblastoma. CSF1R inhibition and reinitiation yields specific restoring of TSPO in TAM and could serve as immunomodulatory therapy strategy.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.669
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
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    EXTH-25. IN VIVO TWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_5 ( 2023-11-10), p. v229-v229
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_5 ( 2023-11-10), p. v229-v229
    Abstract: Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed. METHODS We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing B7-H3 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. B7-H3-directed CAR T-cells were injected into the adjacent brain parenchyma. RESULTS Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against B7-H3 are currently ongoing. CONCLUSIONS We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad179.0878
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 7
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    EXTH-73. IN VIVO EFFECTS OF EPCAM-DIRECTED CAR T CELLS IN COMBINATION WITH PD-1 CHECKPOINT BLOCKADE IN LUNG CANCER BRAIN METASTASIS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_5 ( 2023-11-10), p. v241-v241
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_5 ( 2023-11-10), p. v241-v241
    Abstract: Metastatic lung cancer is incurable once it spreads to the brain. Chimeric antigen receptor (CAR) T cells show promise in hematologic malignancies but face challenges in solid tumors, particularly in brain tumors, due to a highly immunosuppressive tumor microenvironment (TME), tumor antigen (TA) heterogeneity and impeded infiltration and persistence at the tumor site. To test the efficacy of CAR T cells and to find strategies for potentially enhancing its efficacy, CAR T cells were applied with and without checkpoint-blockade to treat lung cancer brain metastasis. METHODS We used an immunocompetent syngeneic orthotopic cerebral metastasis model combined with a chronic cranial window and repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This allowed us to observe fluorescent tumor cells and CAR T cells in vivo at a single cell level over time. We injected red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM-LL/2tdT) into the brain tissue, followed by injection of EpCAM-directed or mock CAR T cells. Animals received anti-PD-1 and the respective isotype control via intraperitoneal injections. RESULTS EpCAM-directed CAR T cells were generated and showed substantial anti-tumor effects in vitro. Local injection into EpCAM-LL/2 tumor-bearing mice led to intratumoral accumulation of CAR T cells, resulting in reduced tumor growth compared to undirected CAR T cells translating into long-term survival in a fraction of animals. However, intratumoral CAR T cell numbers decrease over time pointing towards insufficient persistence. Interestingly, anti-PD-1 treatment did not enhance intratumoral CAR T accumulation, persistence and anti-tumor efficacy. CONCLUSION Our findings demonstrate the great potential of cell-based treatment approaches for the treatment of lung cancer brain metastases and underlines the necessity of further investigations to enhance infiltration and persistence in solid tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad179.0926
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    Significance of molecular diagnostics for therapeutic decision-making in recurrent glioma
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Advances Vol. 5, No. 1 ( 2023-01-01)
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 5, No. 1 ( 2023-01-01)
    Abstract: Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary molecular tumor board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). Methods We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based on next-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens, and outcome parameters were collected. Results Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32–536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), epidermal growth factor receptor amplification (19/73; 26%), and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one-third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. Conclusions In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable antitumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdad060
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 9
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    CAR T-Cells for CNS Lymphoma: Driving into New Terrain?
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 10 ( 2021-05-20), p. 2503-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 10 ( 2021-05-20), p. 2503-
    Abstract: Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13102503
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 10
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    Shunt dependency in supratentorial intraventricular tumors depends on the extent of tumor resection
    Springer Science and Business Media LLC ; 2023
    In:  Acta Neurochirurgica Vol. 165, No. 4 ( 2023-03-02), p. 1053-1064
    Details
    In: Acta Neurochirurgica, Springer Science and Business Media LLC, Vol. 165, No. 4 ( 2023-03-02), p. 1053-1064
    Abstract: Supratentorial intraventricular tumors (SIVTs) are rare lesions of various entities characteristically presenting with hydrocephalus and often posing a surgical challenge due to their deep-seated localization. We aimed to elaborate on shunt dependency after tumor resection, clinical characteristics, and perioperative morbidity. Methods We retrospectively searched the institutional database for patients with supratentorial intraventricular tumors treated at the Department of Neurosurgery of the Ludwig-Maximilians-University in Munich, Germany, between 2014 and 2022. Results We identified 59 patients with over 20 different SIVT entities, most often subependymoma (8/59 patients, 14%). Mean age at diagnosis was 41 ± 3 years. Hydrocephalus and visual symptoms were observed in 37/59 (63%) and 10/59 (17%) patients, respectively. Microsurgical tumor resection was provided in 46/59 patients (78%) with complete resection in 33/46 patients (72%). Persistent postoperative neurological deficits were encountered in 3/46 patients (7%) and generally mild in nature. Complete tumor resection was associated with less permanent shunting in comparison to incomplete tumor resection, irrespective of tumor histology (6% versus 31%, p  = 0.025). Stereotactic biopsy was utilized in 13/59 patients (22%), including 5 patients who received synchronous internal shunt implantation for symptomatic hydrocephalus. Median overall survival was not reached and did not differ between patients with or without open resection. Conclusions SIVT patients display a high risk of developing hydrocephalus and visual symptoms. Complete resection of SIVTs can often be achieved, preventing the need for long-term shunting. Stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms if resection cannot be safely performed. Due to the rather benign histology, the outcome appears excellent when adjuvant therapy is provided.
    Type of Medium: Online Resource
    ISSN: 0942-0940
    URL: Article
    DOI: 10.1007/s00701-023-05532-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1464215-3
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