Expression of HMP/AN2, a melanoma associated antigen, in murine cerebral gliomas: potential for radioimmunotargeting

Paul, Asit K.; Ciesielski, Michael; Sajjad, Munawwar; Wang, Xinhui; Ferrone, Soldano; Abdel-Nabi, Hani; Fenstermaker, Robert A.

doi:10.1007/s11060-009-9798-3

Cited by 7 publications

(3 citation statements)

References 32 publications

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“…The GL261 model has also been widely used in support of vaccine-based studies. GL261 cells express unique tumor antigens, including HMP/AN2, [ 80 ] EphA-2, [ 81 ] and GARC-1, [ 82 ] and these induce a GL261-specific CTL response. GL261 vaccines, used for pulsing DCs, have been curative and, at times, even preventative of tumor engraftment [ 83 - 85 ].…”

Section: Gl261; C57bl/6 Modelmentioning

confidence: 99%

Immunocompetent murine models for the study of glioblastoma immunotherapy

et al. 2014

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Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

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Section: Gl261; C57bl/6 Modelmentioning

confidence: 99%

Immunocompetent murine models for the study of glioblastoma immunotherapy

et al. 2014

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“…Furthermore, this model employs immunocompetent mice, and thus is suitable to analyze GBM tumor immunology and to perform immunotherapeutic research ( 119 ). Among the reported pre-clinical applications of this model, we can mention: the use of adoptive T cell transfers to restore and induce long-term immunity; the use of antibodies to improve antitumor T cell activity via augmentation of costimulatory signals; the abrogation of survival advantages of Tregs; and the enhancement of tumor immunogenicity using IL12 based gene therapy to stimulate robust cytotoxic T cell responses ( 119 ), as GL261 express unique tumor antigens which can induce a specific T cell responses ( 120 ). Moreover, this model has been employed to study the immunosuppressive effects of TGFβ, which promotes Treg activity ( 121 ).…”

Section: Mouse Models To Study Glioma Immune Microenvironment and Possible Therapiesmentioning

confidence: 99%

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

et al. 2021

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High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

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“…Shown in this thesis and by others (Akbasak et al 1991;Wim Maes and Van Gool 2010), MHC class I and class II expression is constitutive or inducible, rendering tumour cells susceptible to T cell recognition. A number of TAA have been described for GL261, including TRP--2 and gp100 (Prins et al 2003), survivin (Ciesielski et al 2008), AN2 (A. K. Paul et al 2009), GARC--1 (Iizuka et al 2006), andEphA2 (Ueda et al 2009) but the immunodominant antigens mediating responses to whole tumour antigen--based vaccines are unknown (Grauer et al 2008). The model has been used extensively to assess active immunotherapies for glioma and has been described as the "gold standard" for this purpose (Wim Maes and Van Gool 2010).…”

mentioning

confidence: 99%

Improving immunotherapy for high grade glioma

Hunn¹

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<p>Glioblastoma multiforme (GBM) is a malignant primary brain tumour that is almost always fatal. Conventional treatment modalities are limited by toxicity. T cell-based immunotherapy is a promising alternative that has the potential to specifically target tumour cells. The author of this thesis was a principal investigator for a recently completed Phase I clinical trial in which patients with recurrent GBM were treated with surgery, dendritic cell-based immunotherapy and chemotherapy. In addition to conducting the trial in collaboration with others, the author used peripheral blood mononuclear cells from trial participants to assess anti-tumour immune responses before and after treatment. A broad correlation was observed between clinical outcome and anti-tumour immunity, with sustained progression-free survival occurring in two patients with baseline responses that persisted or increased after treatment. However, the overall clinical benefit was modest. For progress to be made, there is a need to develop a more potent vaccine. With this in mind, a novel “Glioma-Gal” vaccine was devised and tested in an orthotopic mouse model of glioma, This simple vaccine consisted of irradiated autologous tumour cells pulsed with the glycolipid alpha-galactosylceramide, an immunoadjuvant that induces invariant Natural Killer T cells to licence endogenous dendritic cells. The vaccine was shown to be effective in a therapeutic setting when accompanied by depletion of regulatory T cells. Mechanistically, vaccine efficacy was dependent on CD4 T cells and the mediastinal lymph node was shown to be an important site of T cell priming. It was further shown that components of the immune system necessary for the vaccine to work were present and competent in a cohort of GBM patients. The final chapters explore the idea of enhancing the therapeutic benefit of this vaccine by targeting certain tumour cell subsets or phenotypes. Cancer stem cells (CSC) are proposed to be a subset of tumour cells with a unique capacity for initiating and maintaining tumours. Eliminating these cells may therefore be both necessary and sufficient to achieve cure. Using the same mouse model, a variety of methods were assessed for their ability to isolate or enrich for a CSC subset. Of these, culture in serum-free medium in the presence of certain growth factors was shown to enrich for a more stem cell-like phenotype. However, a vaccine constructed from these stem cell-like cells was not more effective than the standard vaccine. Next, the author tested the hypothesis that a vaccine manipulated to target chemoresistant cells would be more effective than standard vaccine when used in combination with chemotherapy. However, the modified vaccine showed no advantage over standard vaccine in this model. In the course of these experiments, synergy was observed between the vaccine and the chemotherapy agent doxorubicin. The mechanism responsible for this supra-additive effect remains undetermined but is most likely due to an immunomodulatory effect of low dose doxorubicin. The Glioma-Gal vaccine design holds promise but more studies are needed to realise the full potential of this approach. The data presented in the thesis did not support targeting CSC or chemoresistant cells as ways of achieving this. In contrast, combining the vaccine with immunomodulation was effective and merits further exploration.</p>

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Expression of HMP/AN2, a melanoma associated antigen, in murine cerebral gliomas: potential for radioimmunotargeting

Cited by 7 publications

References 32 publications

Immunocompetent murine models for the study of glioblastoma immunotherapy

Immunocompetent murine models for the study of glioblastoma immunotherapy

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

Improving immunotherapy for high grade glioma

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