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  • American Association for Cancer Research (AACR)  (4)
  • 2015-2019  (4)
  • 1
    Online Resource
    Online Resource
    Utility of the RIG-I Agonist Triphosphate RNA for Melanoma Therapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12 ( 2019-12-01), p. 2343-2356
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12 ( 2019-12-01), p. 2343-2356
    Abstract: The pattern recognition receptor RIG-I plays an important role in the recognition of nonself RNA and antiviral immunity. RIG-I's natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. In this study, we present comprehensive data validating the concept and utility of treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Using mRNA expression data of human tumors, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Furthermore, we confirm susceptibility of cancer cells to ppp-RNA treatment in different cellular models of human melanoma, revealing unexpected heterogeneity between cell lines in their susceptibility to RNA agonist features, including sequence, secondary structures, and presence of triphosphate. Cellular responses to RNA treatment (induction of type I IFN, FasR, MHC-I, and cytotoxicity) were demonstrated to be RIG-I dependent using KO cells. Following ppp-RNA treatment of a mouse melanoma model, we observed significant local and systemic antitumor effects and survival benefits. These were associated with type I IFN response, tumor cell apoptosis, and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen–specific CTLs following treatment with RIG-I agonists. Despite potential challenges in the generation and formulation of potent RIG-I agonists, ppp-RNA or analogues thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-18-1262
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 5024: Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5024-5024
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5024-5024
    Abstract: RIG-I is a highly important cytosolic pattern recognition receptor (PRR) involved in sensing RNA virus infection and inducing interferon (IFN) production. RIG-I’s natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. This study validates the use of intratumoral treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Firstly, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Secondly, cellular models of human melanoma confirm susceptibility of cancer cells to ppp-RNA treatment, revealing unexpected heterogeneity between cell lines in their selectivity for RNA features, including sequence, secondary structures and presence of triphosphate. Cellular RNA treatment responses (type I IFN, FasR, MHC-I, cytotoxicity) were demonstrated to be RIG-I dependent using RIG-I KO cells. Thirdly, we show that ppp-RNA treatment of a mouse melanoma tumor model, leads to significant local and systemic anti-tumor effects and survival benefits, associated with a type I IFN response, tumor cell apoptosis and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen specific CTLs following treatment with RIG-I agonist. Overall our study demonstrates that ppp-RNA or analogs thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy. However, potential challenges in the generation and formulation of potent RIG-I agonists remain to be solved. Citation Format: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner. Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5024.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-5024
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    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
    Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 21 ( 2015-11-01), p. 4483-4493
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 21 ( 2015-11-01), p. 4483-4493
    Abstract: The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I–like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy. Cancer Res; 75(21); 4483–93. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-3499
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 19 ( 2019-10-01), p. 5890-5900
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 19 ( 2019-10-01), p. 5890-5900
    Abstract: Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing. Experimental Design: BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell–induced lysis were characterized in three murine and human tumor models in vitro and in vivo. Results: Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo. Conclusions: We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-3927
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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