1. 1-23 of 23
    1. Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies

      Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies

      A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities.

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    2. Network Modeling of microRNA-mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN

      Network Modeling of microRNA-mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN

      Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma.

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      Mentions: Imaging MYCN Genetics
    3. Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma

      Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma

      Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions.

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      Mentions: MYCN
    4. CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1-Mediated ERK and BCL2/Cyclin D1 Pathways

      CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1-Mediated ERK and BCL2/Cyclin D1 Pathways

      CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells.

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      Mentions: Tumorigenesis
    5. Long Noncoding RNA pancEts-1 Promotes Neuroblastoma Progression through hnRNPK-Mediated {beta}-Catenin Stabilization

      Long Noncoding RNA pancEts-1 Promotes Neuroblastoma Progression through hnRNPK-Mediated {beta}-Catenin Stabilization

      Long noncoding RNAs (lncRNA) play essential roles in tumor progression. However, the functions of lncRNAs in the tumorigenesis and aggressiveness of neuroblastoma still remain to be determined. Here, we report the identification of lncRNA pancEts-1 as a novel driver of neuroblastoma progression by using a public microarray dataset. LncRNA pancEts-1 promoted the growth, invasion, and metastasis of neuroblastoma cells in vitro and in vivo.

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    6. PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma

      Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma.

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      Mentions: MYCN Tumorigenesis
    7. Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors

      Chimeric antigen receptor–modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing.

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      Mentions: Antibody PD-1
    8. Therapeutic Potential of Bacteria against Solid Tumors

      Intentional bacterial infections can produce efficacious antitumor responses in mice, rats, dogs, and humans. However, low overall success rates and intense side effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the proinflammatory cytokine TNFα in a set of established murine models of cancer.

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      Mentions: Side Effects
    9. Intrinsic Resistance of Solid Tumors to Immune Checkpoint Blockade Therapy

      Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. Mechanistically, the number of mutations determines tumor immunogenicity.

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    10. T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNF{alpha} Expression and Empower Adoptive Cell Therapy for Solid Tumors

      Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene–engineered lymphocytes.

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    11. A Metastatic Mouse Model Identifies Genes That Regulate Neuroblastoma Metastasis

      Metastatic relapse is the major cause of death in pediatric neuroblastoma, where there remains a lack of therapies to target this stage of disease. To understand the molecular mechanisms mediating neuroblastoma metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate malignant cell subpopulations with a higher propensity for metastasis to bone and the central nervous system.

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      Mentions: Relapse Metastasis
    12. Metabolic Adaptation in High-Risk Neuroblastoma Lacking p53

      Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease.

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      Mentions: Relapse
    13. PD1CD28 Augments CAR T-cell Therapy for Solid Tumors

      "We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, “PD1CD28,” on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to ...

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      Mentions: Treatment
    14. Targeting the NPTX2/NPTXR Pathway in Neuroblastoma

      "We show that, in comparison with normal tissues, NPTX2 and NPTXR are overexpressed in vivo in mouse models, as well as in human Schwannian stroma-poor, stage IV neuroblastoma. Both proteins are concentrated in the vicinity of tumor blood vessels, with NPTXR also present on neuroblastic tumor cells. In vivo targeting of NPTX2 and NPTXR with the selected peptide or with specific antibodies reduces tumor burden in orthotopic mouse models of human neuroblastoma. In vitro interference with this ligand/receptor system inhibits the organization of neuroblastoma cells in tumor-like masses in close contact with vascular cells, as well as their adhesion ...

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    15. G-CSF Is a Cancer Stem Cell-Specific Growth Factor--Response

      "Based on our observations demonstrating critical biologic effects of G-CSF/STAT3 signaling on this tumor subpopulation, we agree that additional clinical and preclinical research is required. However, we respectfully maintain that our findings should prompt a discussion and reevaluation of the risks and benefits of G-CSF in high-risk neuroblastoma. This is especially true as advances in supportive care (e.g., antibiotic/antifungal therapies, and patient monitoring) have altered the risks of neutropenia in our pediatric patient population over the past decade. As always, new biologic findings need to be validated and incorporated into revised risk/benefit calculations and communicated to ...

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      Mentions: G-CSF
    16. G-CSF Is a Cancer Stem Cell-Specific Growth Factor--Letter

      "Taken together, we strongly recommend that there be no deviation from the current practice of using G-CSF to abrogate the infectious complications of the highly dose-intensive chemotherapy backbone used to treat high-risk neuroblastoma patients around the world. Unwarranted removal of G-CSF has the potential to directly increase patient morbidity and mortality."

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      Mentions: G-CSF
    17. Genome Editing for Allogenic Adoptive T-cell Immunotherapy

      "Functionally, T cells manufactured with this process do not mediate graft-versus-host reactions and are rendered resistant to destruction by alemtuzumab. These characteristics enable the administration of alemtuzumab concurrently or prior to engineered T cells, supporting their engraftment. Furthermore, endowing the TALEN-engineered cells with a CD19 CAR led to efficient destruction of CD19+ tumor targets even in the presence of the chemotherapeutic agent. These results demonstrate the applicability of TALEN-mediated genome editing to a scalable process, which enables the manufacturing of third-party CAR T-cell immunotherapies against arbitrary targets. As such, CAR T-cell immunotherapies can therefore be used in an “off-the-shelf” manner ...

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      Mentions: Immunotherapy
    18. Affinity-Tuned CARs Increased Therapeutic Index

      Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissues that express it at physiologic levels. A CAR-expressing T-cell panel was generated with target antigen affinities varying over three orders of magnitude.

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      Mentions: T-Cells
    19. Treatment-Induced Metastasis

      The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits.

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    20. Neuroblastoma Arginase-Dependent Microenvironment

      Neuroblastoma is the most common extracranial solid tumor of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumor cells suppress T-cell proliferation through increased arginase activity.

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    21. PD-L1 Imaging

      "Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti–PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3.1 was radiolabeled with Indium-111 (111In) and characterized using PD-L1–expressing MDA-MB-231 cells."

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    22. Regulating Fate Decisions of Anticancer T Cells

      A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting.

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    23. Stratifying Cancers for Immunotherapy

      Cancer immunotherapy may become a major treatment backbone in many cancers over the next decade. There are numerous immune cell types found in cancers and many components of an immune reaction to cancer. Thus, the tumor has many strategies to evade an immune response. It has been proposed that four different types of tumor microenvironment exist based on the presence or absence of tumor-infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression.

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      Mentions: Immunotherapy PD-1
    1-23 of 23
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