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  • 1
    Online Resource
    Online Resource
    Abstract 2038: Epstein-Barr virus shapes the tumor microenvironment in classical Hodgkin lymphoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2038-2038
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2038-2038
    Abstract: The histopathologic appearance of classical Hodgkin lymphoma (cHL) is characterized by rare multinucleated malignant Hodgkin Reed-Sternberg (HRS) cells within a rich inflammatory tumor microenvironment (TME). A subset of cHL cases are associated with Epstein-Barr virus (EBV) infection, which is considered to play a part in cHL pathogenesis. Since EBV+ and EBV- cHL exhibit differing mechanisms of pathogenesis, we hypothesized that the composition and spatial architecture of the TME in EBV-associated cHL differs from that of EBV- cHL, with implications for stratifying patients for specific treatment regimens based on EBV positivity. Here, we designed a multimodal approach using spatially resolved multiplexed protein profiling, flow cytometry, immunohistochemistry, and transcriptomics to profile EBV positive and EBV negative cHL tumors. We measured over 27 million single cells and 1,000 unique proteomic cell states derived using 29 proteins in addition to the transcriptome in 43 patient tumors. We uncovered significant differences between EBV+ and EBV- cHL in relative abundance of specific immune cell types, immune activation state, and spatial organization of the HRS cell neighborhoods. We present a multidimensional characterization of cHL in relation to EBV with implications for therapeutic stratification of patients with virus-associated cHL. Citation Format: Maryam Pourmaleki, Caitlin J. Jones, Sabrina D. Mellinghoff, Brian Greenstein, Priyadarshini Kumar, Mikhail Roshal, Travis J. Hollmann, Nicholas D. Socci, Ahmet Dogan, Ingo K. Mellinghoff. Epstein-Barr virus shapes the tumor microenvironment in classical Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2038.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2038
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 2125: Towards a spatial view of immune cell function in cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2125-2125
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2125-2125
    Abstract: Immunotherapy can result in lasting tumor regressions, but despite its success, only a subset of patients and cancer types benefit from immunotherapy. Thus, uncovering features of the tumor microenvironment (TME) that contribute to this differential response can inform candidates for novel therapies and biomarkers for patient stratification. Recent advances in single-cell technologies allow for profiling of cell states and their spatial interactions within a tumor. Here, we performed multiplexed immunofluorescence (mpIF), a method for in situ single-cell measurement of 30+ proteins, as well as bulk transcriptomics and genomics on 180 tumor samples across 4 immunotherapy-responsive and -resistant solid and liquid cancers: in-transit melanoma (ITM), non-small cell lung cancer (NSCLC), glioblastoma multiforme (GBM), and classical Hodgkin lymphoma (cHL). In aggregate, we measured over 100 million single cells and identified over 1,000 unique tumor and immune cell states. We uncovered immune-suppressive cell states, such as macrophages negative for PD-L1 and B7-H3 in immunotherapy-resistant ITM tumors and all GBM tumors, which generally fail to respond to immunotherapy. In GBM, macrophages exhibited two distinct spatial topologies, infiltrated or excluded. In ITM, we identified pre-treatment cell states and gene expression signatures that associate with immunotherapy response such as MHC class I expression on the tumor cell surface, B cell aggregates, “exhausted” PD-1/LAG-3/TIM-3 triple-positive CD8+ T cells, and expression of interferon-gamma genes. We observed a similar immune checkpoint-rich (PD-1/LAG-3/TIM-3 triple-positive) TME in all cHL tumors, which have remarkably high immunotherapy response rates. We spatially defined the microniche (30-micron radius neighborhood) of “exhausted” CD8+ T cells, and within the microniches, found antigen presentation competent tumor cells, proliferating T cells, and B7-H3 positive macrophages, which together contribute to an activated TME. Together, we present a statistical workflow for the integrated analysis of spatially resolved multidimensional data for cancer target discovery that is tailored towards application in routinely collected formalin-fixed paraffin-embedded cancer biospecimens. Citation Format: Maryam Pourmaleki, Caitlin J. Jones, Brian D. Greenstein, Sabrina D. Mellinghoff, Daniel A. Navarrete, Smrutiben A. Mehta, Nicholas D. Socci, Ingo K. Mellinghoff, Travis J. Hollmann. Towards a spatial view of immune cell function in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2125.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-2125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS2078-TPS2078
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS2078-TPS2078
    Abstract: TPS2078 Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. GBM AGILE has screened over 1000 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. While enrollment had an initial dip during the early stages of the pandemic (April-May, 2020), with flexible processes including remote based monitoring, minimizing in person visits, and remote provision of IMP, the enrollment rebounded by June, 2020. Through the use of improved and efficient processes allowed within a master protocol/adaptive platform trial infrastructure, GBM AGILE has been seamlessly operating a global trial during a global pandemic. Clinical trial information: NCT03970447.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS2078
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Identification of the JNK Signaling Pathway as a Functional Target of the Tumor Suppressor PTEN
    Elsevier BV ; 2007
    In:  Cancer Cell Vol. 11, No. 6 ( 2007-06), p. 555-569
    Details
    In: Cancer Cell, Elsevier BV, Vol. 11, No. 6 ( 2007-06), p. 555-569
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccr.2007.04.021
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis
    Elsevier BV ; 2009
    In:  Cancer Cell Vol. 16, No. 1 ( 2009-07), p. 44-54
    Details
    In: Cancer Cell, Elsevier BV, Vol. 16, No. 1 ( 2009-07), p. 44-54
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccr.2009.05.009
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2009
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Balancing Risk and Efficiency in Drug Development for Rare and Challenging Tumors: A New Paradigm for Glioma
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 30 ( 2022-10-20), p. 3510-3519
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 30 ( 2022-10-20), p. 3510-3519
    Abstract: The process of developing cancer therapies is well established and has enabled the incorporation of many new drugs and classes of agents into the standard of care for common cancers. Clinical drug development is fundamentally different for rare and difficult-to-treat solid tumors, such as glioma or pancreatic cancer. The failure to develop effective new agents for the latter diseases has discouraged the development of therapeutics for these cancers. Using glioma as an example, we describe a process toward obtaining more reliable early-stage signals of drug activity and a process toward translating those signals into clinical benefits with more efficient late-stage development. If linked together, these processes should increase the likelihood of benefit in late-stage settings at a lower cost and encourage more drug development for patients with rare and difficult-to-treat cancers.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.21.02166
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    Ivosidenib in Isocitrate Dehydrogenase 1 – Mutated Advanced Glioma
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 29 ( 2020-10-10), p. 3398-3406
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 29 ( 2020-10-10), p. 3398-3406
    Abstract: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs ( 〉 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.19.03327
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 8
    Online Resource
    Online Resource
    A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 2003-2003
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 2003-2003
    Abstract: 2003 Background: AG-120 (ivosidenib [IVO]) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) evaluated in 66 glioma patients (pts) in an ongoing phase 1 study. AG-881 (vorasidenib [VOR] ) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 evaluated in 52 glioma pts in an ongoing phase 1 study. In an orthotopic glioma model, IVO and VOR reduced 2-hydroxyglutarate (2-HG) by 85% and 98%, respectively, despite different brain:plasma ratios ( 〈 0.04 vs 1.33). Methods: Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment in mIDH1 low-grade glioma. Pts with recurrent non-enhancing WHO-2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment for 4 wks preoperatively in Cohort 1. Post-operatively, pts continued to receive IVO or VOR and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared to control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Pts with non-evaluable tissue were replaced. Results: As of 29 Nov 2018, 26 pts (17M, 9F; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5), 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed with 16 evaluable. Common ( 〉 10%) TEAEs (all grade 1/2): diarrhea (36%), hypocalcemia and constipation (each 20%), anemia, hyperglycemia, pruritus, headache and nausea (each 16%), and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio: 0.16 for IVO, 2.4 for VOR. Tumor 2-HG results are shown in Table. Updated data from Cohort 1 will be presented. Conclusions: In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered 2-HG compared to untreated samples. Cohort 2 is open and will evaluate IVO 250mg BID and VOR 10mg QD. Brain tumor 2-HG concentration. Clinical trial information: NCT03343197. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.2003
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 9
    Online Resource
    Online Resource
    Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 2012-2012
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2012-2012
    Abstract: 2012 Background: XL765 is a potent pan PI3K inhibitor with activity against mTOR and XL147 is a potent pan-PI3K inhibitor. Inhibition of the PI3K/mTOR pathway may be beneficial in the treatment of GBM. Methods: Patients with GBM who were candidates for a surgical resection were eligible for this exploratory study. Cohorts of 6-10 patients were treated with one of three regimens: Cohort 1: XL765 50mg twice daily (BID), Cohort 2: XL147 200mg once daily (QD), Cohort 3: XL765 90mg QD for 〉 10 days prior to undergoing tumor resection. Tumor tissue was obtained at ~12, 24 and 3 hours after the last dose, respectively. Frozen tumor tissue and blood were analyzed for drug concentration (PK) and pathway modulation was analyzed in post-dose frozen tumor tissue and compared to reference tumor samples from GBM patients not treated with XL765 or XL147. Pharmacodynamic impact (PD) on the pathway, apoptosis and proliferation was examined by immunohistochemistry (IHC) in an FFPE tumor sample from each patient and compared to an archived tumor sample from an earlier surgery. Results: Enrollment is complete with 21 patients enrolled; 6, 6 and 7 were evaluable for the PK/PD analysis in cohorts 1, 2 and 3, respectively. The toxicity profiles for both drugs were consistent with previous studies. PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2. Reduction in Ki67 was observed in 6/6 and 5/7 patients in cohorts 1 and 3 and 4/6 patients in cohort 2. Conclusions: XL765 when given on a QD or BID schedule to patients with glioma yields moderately higher distribution of XL765 into CNS tumor compared to XL147 based on tumor to plasma ratios. Decreases in pS6K1, consistent with pathway inhibition, and decreases in Ki67, consistent with inhibition of proliferation, were observed following treatment with both XL147 and XL765. Clinical trial information: NCT01240460.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.2012
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 10
    Online Resource
    Online Resource
    Phase 1 study of AG-881, an inhibitor of mutant IDH1/IDH2, in patients with advanced IDH-mutant solid tumors, including glioma.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 2002-2002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 2002-2002
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.2002
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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