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  • 1
    Online Resource
    Online Resource
    Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 48 ( 2019-11-26), p. 24275-24284
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 48 ( 2019-11-26), p. 24275-24284
    Abstract: T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1903854116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 2
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    Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention
    Elsevier BV ; 2019
    In:  Cancer Cell Vol. 36, No. 3 ( 2019-09), p. 250-267.e9
    Details
    In: Cancer Cell, Elsevier BV, Vol. 36, No. 3 ( 2019-09), p. 250-267.e9
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2019.08.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 3
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    Early CT perfusion mismatch in acute stroke is not time-dependent but relies on collateralization grade
    Springer Science and Business Media LLC ; 2016
    In:  Neuroradiology Vol. 58, No. 4 ( 2016-4), p. 357-365
    Details
    In: Neuroradiology, Springer Science and Business Media LLC, Vol. 58, No. 4 ( 2016-4), p. 357-365
    Type of Medium: Online Resource
    ISSN: 0028-3940 , 1432-1920
    URL: Article
    DOI: 10.1007/s00234-016-1643-8
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
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  • 4
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    Color-Coded Cerebral Computed Tomographic Angiography : Implementation of a Convolution-Based Algorithm and First Clinical Evaluation in Patients With Acute Ischemic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Investigative Radiology Vol. 50, No. 5 ( 2015-05), p. 361-365
    Details
    In: Investigative Radiology, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 5 ( 2015-05), p. 361-365
    Type of Medium: Online Resource
    ISSN: 0020-9996
    URL: Article
    DOI: 10.1097/RLI.0000000000000134
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 5
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    Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 4 ( 2016-04-01), p. 702-710
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 4 ( 2016-04-01), p. 702-710
    Abstract: Patients with nonsquamous non–small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti–VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases–preventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR = 0.36, P & lt; 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti–VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases. Mol Cancer Ther; 15(4); 702–10. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-15-0582
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    Abstract 3605: Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3605-3605
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3605-3605
    Abstract: Background and Rationale: Leptomeningeal carcinomatosis is a cause of major morbidity and mortality in many solid malignancies. Therapeutic options are limited and include radiation therapy as well as intrathecal administration of cytotoxic agents. Accordingly, novel diagnostic and therapeutic modalities are needed in order to improve the prognosis of patients diagnosed with leptomeningeal carcinomatosis. Liquid biopsies are safe and offer great potential to define actionable targets in a variety of cancers. However, a role for liquid biopsies from cerebral spine fluid (CSF) has not been defined to date. Patients and Methods: CSF samples from ten consecutive patients diagnosed with leptomeningeal carcinomatosis were collected as part of clinical routine and evaluated by next generation sequencing. All cases were discussed in the Molecular Tumorboard (MTB) as part of the “Molecular Diagnostics and Therapy” unit at the Comprehensive Cancer Center Munich. Results: Samples from patients diagnosed with cholangiocarcinoma (1), ewing's sarcoma (1), breast (5), lung (2) and gastric cancer (1) were submitted for panel sequencing. Sequencing was technically successful in nine out of ten patients and circulating tumor DNA (ctDNA) was found in all of these nine patients. Of note, ctDNA was also detectable in cases in which microscopy did not reveal malignant cells in the CSF sample (4/10 cases). Tumorigenic alterations were found in seven out of these nine patients. Importantly, NGS of cerebral spine fluid detected previously unknown and therapeutically relevant alterations in this cohort. Case discussion in the Molecular Tumorboard led to therapeutic recommendations in three cases and targeted therapy was ultimately initiated in one case. Conclusions: Next generation sequencing from cerebral spine fluid is feasible in clinical practice and yields tumorigenic alterations in a large fraction of patients. Importantly, our approach demonstrated the therapeutic relevance of this approach in patients with leptomeningeal carcinomatosis. Citation Format: Louisa von Baumgarten, Anna Reischer, Jörg Kumbrink, Andreas Jung, Sibylle Liebmann, Steffen Ormanns, Klaus Metzeler, Julian Holch, Volker Heinemann, Thomas Kirchner, Benedikt Westphalen. Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3605.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3605
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
    Online Resource
    Online Resource
    Diagnostic accuracy of whole-brain CT perfusion in the detection of acute infratentorial infarctions
    Springer Science and Business Media LLC ; 2016
    In:  Neuroradiology Vol. 58, No. 11 ( 2016-11), p. 1077-1085
    Details
    In: Neuroradiology, Springer Science and Business Media LLC, Vol. 58, No. 11 ( 2016-11), p. 1077-1085
    Type of Medium: Online Resource
    ISSN: 0028-3940 , 1432-1920
    URL: Article
    DOI: 10.1007/s00234-016-1743-5
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
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  • 8
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    Abstract A21: Chimeric antigen receptor T cells targeting primary CNS lymphoma: Visualizing the anti-tumor response in vivo
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Immunology Research Vol. 5, No. 3_Supplement ( 2017-03-01), p. A21-A21
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 5, No. 3_Supplement ( 2017-03-01), p. A21-A21
    Abstract: Introduction: Advances in the treatment of primary CNS lymphoma (PCNSL) have led to prolonged survival. However, long-term remission is achieved infrequently. Chimeric antigen receptor T cells (CAR T cells) have proven to be a promising therapeutic approach for systemic B cell malignancies. Even in patients with advanced chemotherapy-refractory disease, syngeneic or allograft-derived CAR T cells can achieve durable remission. The most successful CAR targets CD19, a pan-B cell antigen also expressed in PCNSL. Whether CAR T cells are able to control PCNSL growth, and if so, if allogeneic or syngeneic CAR T cells are equally effective is not known. Additionally, information on the exact cellular interactions leading to tumor regression remains scarce. Methods: To analyze the therapeutic effect of CAR T cells on orthotopic PCNSL at single-cell resolution in vivo, we established a novel mouse model. After microsurgical preparation of a cranial window, human red fluorescent B-cell lymphoma cells were stereotactically implanted into the cortex of nude mice. After the tumour reached a threshold diameter, we injected green fluorescent CAR T cells adjacent to the tumour. To unravel the ensuing CAR T cell - tumor interactions, we performed in vivo imaging using dual photon microscopy over several weeks. Results: After implantation, allogeneic as well as syngeneic CAR T cells migrate throughout both hemispheres and preferentially accumulate in the subarachnoid compartment. Over time, CAR T cells infiltrate the tumor in high numbers. Upon encountering their cognate antigen, CAR T cells proliferate, their migration velocity decreases and they arrest in close contact with tumour cells. Cell-cell interactions can be observed in real time and are accompanied by tumor regression. Control CAR T cells, lacking the extracellular domain of the CAR, infiltrate the tumor in lower numbers and barely arrest, proliferate or kill tumor cells. After several weeks, allogeneic CAR T cells disappear and persisting lymphoma cells lead to tumor regrowth. However, repeated therapy with CAR T cells remains successful. Syngeneic CAR T cells show longer persistence and improved efficacy compared to allogeneic CAR T cells. Conclusions: For the first time, CAR T cell interactions with tumor cells have been visualized repeatedly over several weeks. In vivo microscopy reveals important aspects of CAR T cell biology. Long-term analysis indicates that CAR T cells are generally able to control PCNSL growth. Allogeneic CAR T cells show lower persistence than syngeneic T cells. These findings corroborate preclinical data suggesting that CAR expression does not protect against allogeneic T cell deletion. However, syngeneic CAR T cell therapy as well as repeated therapy with allogeneic CAR T cells reduces tumor growth, indicating persistence as a key factor limiting efficacy of CAR T cell therapy in PCNSL. These results emphasize the need for new strategies to enhance CAR T cell persistence. Citation Format: Matthias Mulazzani, Simon Fräßle, Veit Buchholz, Andreas Straube, Dirk Busch, Louisa von Baumgarten. Chimeric antigen receptor T cells targeting primary CNS lymphoma: Visualizing the anti-tumor response in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A21.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM16-A21
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 9
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    High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Support for Relapsed or Refractory Primary CNS Lymphoma - a Prospective Multicentre Trial By the German Cooperative PCNSL Study Group
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 781-781
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 781-781
    Abstract: Purpose To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in patients with relapsed or refractory primary CNS lymphoma (PCNSL). Patients and methods We conducted a single-arm multicentre phase 2 study for immunocompetent patients ( 〈 66 years of age) with PCNSL failing prior HD-MTX based chemotherapy. Induction treatment consisted of 2 courses of rituximab (rituximab 375mg/m2), high-dose cytarabine (2 x 3g/m2) and thiotepa (40mg/m2) with collection of autologous stem cells in between. Conditioning treatment for HCT-ASCT consisted of rituximab 375mg/m2, carmustine 400mg/m2 and thiotepa (4 x 5mg/kg). Patients commenced HCT-ASCT irrespective of response status after induction. Only patients not achieving complete remission (CR) after HCT-ASCT received whole brain radiotherapy (WBRT). The primary endpoint was CR after HCT-ASCT by intention-to-treat (ITT). Secondary endpoints included safety, progression free survival (PFS, time to progression or death) and overall survival (OS, time to death due to any cause). Results Between May 2007 and July 2012, we enrolled 39 patients from 12 German centres. The median age and Karnofsky performance score was 57 years (range 37 to 65) and 90% (range 60% to 100%), respectively. 28 (71.8%) patients had relapsed and 8 (28.2%) refractory disease. 22 (56.4%) patients responded to induction (4 CR, 18 partial remissions [PR]) and 32 (82.1%) patients commenced HCT-ASCT. 22 patients (56.4%, 95% CI 39.6% to 72.2%) achieved CR after HCT-ASCT, 6 (15.4%) achieved PR, and 1 (2.6%) had stable disease. In 9 (17.8%) patients the final scan was not done, because 7 (18.0%) did not undergo HCT-ASCT and 2 died (5.1%) during HCT-ASCT procedure. After a median follow-up of 45.2 months, the respective 2-year PFS and OS rates were 46.0% (95% CI 30.3% to 61.7%, median PFS 12.4 months, Figure 1) and 56.4% (95% CI 40.8% to 72.0%); median OS not reached (Figure 2). The non-relapse mortality rate was 10.3% (95% CI 4.1% to 26.0%) at 1 year without any further increase afterwards. In the subset of 32 patients who received HCT-ASCT, 14 (56.3%) experienced progression or died translating into 1 and 2-year PFS rates (calculated from date of HCT-ASCT) of 62.5% (95% CI 45.7% to 79.3%) and 56.1% (95% CI 38.8% to 73.3%) with no further decrease afterwards. Main grade 3 or higher toxicities were hematological as expected. We recorded four (10.3%) treatment-related deaths, 2 during induction and 2 during HCT-ASCT. Conclusions In eligible PCNSL patients failing HD-MTX based chemotherapy, a short induction with high-dose cytarabine and thiotepa followed by HCT-ASCT is an effective treatment option. Our data provide a reliable benchmark for future comparative studies needed to further scrutinize the role of HCT-ASCT in the salvage setting for PCNSL. Figure 1. Progression free survival Figure 1. Progression free survival Figure 2. Overall survival Figure 2. Overall survival Disclosures Kasenda: Riemser: Other: Travel Support. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Stilgenbauer:Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.781.781
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 10
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    The Diagnosis and Treatment of Primary CNS Lymphoma
    Deutscher Arzte-Verlag GmbH ; 2018
    In:  Deutsches Ärzteblatt international ( 2018-06-22)
    Details
    In: Deutsches Ärzteblatt international, Deutscher Arzte-Verlag GmbH, ( 2018-06-22)
    Type of Medium: Online Resource
    ISSN: 1866-0452
    URL: Article
    DOI: 10.3238/arztebl.2018.0419
    Language: German
    Publisher: Deutscher Arzte-Verlag GmbH
    Publication Date: 2018
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