Our primary goal is to develop safe and effective immunotherapy strategies for central nervous system (CMS) tumors, such as malignant gliomas. We believe that the systemic induction of anti-tumor immune responses by peripheral vaccines should be combined with modalities that enhance the homing of, and the function of vaccine-induced effector cells within CNS tumor sites. To this end, we believe that polyinosinic-polycytidylic acid stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) is an attractive agent exhibiting the capability to induce inflammatory cytokines/chemokines such as interferon (IFN)-alpha. Using GL261 mouse glioma, we will evaluate our hypothesis that poly-ICLC will enhance the effect of peripheral vaccinations with glioma-associated antigen (GAA)-derived, cytotoxic T lymphocyte (CTL)-epitopes by promoting not only the proliferation of GAA-specific CTLs, but also the promotion of homing receptor/integrin molecule expression by T cells that are critical for their tropism and infiltration into the CNS tumors, such as expression of very late antigen [VLA]-4. However, the therapeutic efficacy of the combination approach with GAA-vaccine and poly-ICLC may remain suboptimal due to tumor-induced immuno-suppressive mechanisms, such as induction of Indoleamine 2,3 dioxygenase (IDO), which may be triggered by poly-ICLC administration. We will therefore determine whether specific blockade of these mechanisms can improve the efficacy of the combinational approach. Even though we believe that our proposed GAA-targeted strategies will be carried out safely without significant CNS-autoimmunity, we will also carefully determine the absence of auto-immune encephalitis. It is becoming increasingly clear that single modality therapies are sub-optimal in the cancer setting and that combinational regimens which coordinately impact the immune system at multiple levels must be prospective^ developed if significant clinical benefit is to be achieved using such approaches. Our central hypothesis is that poly-ICLC, which has been previously clinically evaluated, can be effectively combined with GAA-specific vaccine strategies as well as modulation of other immunological mechanisms, thereby providing a greater index of therapeutic efficacy (versus single-agent regimens). These preclinical studies will provide us with valuable information for our prospective clinical trials with this approach in patients with glioma.
Our specific aims are:
Specific Aim 1 : To determine whether poly-ICLC treatment can serve as an effective """"""""adjuvant"""""""" to peripheral anti-CNS tumor-vaccines by enhancing the induction of anti-glioma CTLs and their consequent infiltration of CNS tumors Specific Aim 2: To develop strategies to improve the efficacy of GAA-DC-vaccines and poly-ICLC co-treatment by counteracting the compensatory, suppressive immunity within the CNS microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055140-03
Application #
7661402
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2007-07-01
Project End
2011-02-14
Budget Start
2009-07-01
Budget End
2011-02-14
Support Year
3
Fiscal Year
2009
Total Cost
$324,844
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Kohanbash, Gary; Carrera, Diego A; Shrivastav, Shruti et al. (2017) Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest 127:1425-1437
Kosaka, Akemi; Ohkuri, Takayuki; Ikeura, Maki et al. (2015) Transgene-derived overexpression of miR-17-92 in CD8+ T-cells confers enhanced cytotoxic activity. Biochem Biophys Res Commun 458:549-554
Ahn, Brian; Kohanbash, Gary; Ohkuri, Takayuki et al. (2015) Histamine deficiency promotes accumulation of immunosuppressive immature myeloid cells and growth of murine gliomas. Oncoimmunology 4:e1047581
Ohkuri, Takayuki; Ghosh, Arundhati; Kosaka, Akemi et al. (2015) Protective role of STING against gliomagenesis: Rational use of STING agonist in anti-glioma immunotherapy. Oncoimmunology 4:e999523
Ohkuri, Takayuki; Ghosh, Arundhati; Kosaka, Akemi et al. (2014) STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2:1199-208
Kosaka, Akemi; Ohkuri, Takayuki; Okada, Hideho (2014) Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells. Cancer Immunol Immunother 63:847-57
Ohno, Masasuke; Ohkuri, Takayuki; Kosaka, Akemi et al. (2013) Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. J Immunother Cancer 1:21
Kohanbash, Gary; McKaveney, Kayla; Sakaki, Masashi et al. (2013) GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-*. Cancer Res 73:6413-23
Okada, Hideho; Scheurer, Michael E; Sarkar, Saumendra N et al. (2013) Integration of epidemiology, immunobiology, and translational research for brain tumors. Ann N Y Acad Sci 1284:17-23

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