The long term goal of Project 2 is to develop safe and effective immunotherapy strategies for CNS tumors incorporating multi-disciplinary approaches that are being pursued in Projects 1 and 3. Despite the feasibility and safety of cancer vaccine-approaches, current evidence suggests that the systemic induction of anti-tumor immune responses by peripheral vaccines should be combined with modalities that enhance the homing and function of vaccine-induced effector cells within CNS tumor sites. Indeed, our studies from the prior funding period have indicated that genetic delivery of interferon (IFN)-alpha into CNS tumors facilitates the tumor-homing and therapeutic efficacy of Type-1 cytotoxic T-lymphocytes (CTLs) in an IFN-inducible protein (IP)-10 dependent manner. More relevant, underlying """"""""prime-boost"""""""" regimen may be achieved in a more clinically feasible manner via administration of a """"""""natural"""""""" inducer of IFN-alpha within the CNS-environment, such as a toll-like receptor (TLR)3 ligand, polyinosinic-polycytidylic acid (poly-IC), stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC). Our preliminary studies with the GL261 glioma model have demonstrated that intramuscular (i.m.) administration of poly-ICLC improves the therapeutic effect of vaccinations with GL261-derived glioma-associated antigen (GAA) CTL epitopes by enhancing the homing of IFN-gamma expressing antigen-specific CTLs to the CNS tumor site. Based on the property of poly-ICLC to induce IFNs as well as IP-10, we hypothesize that administration of poly-ICLC effectively induces Type-1 GAA-specific effector cells as well as IP-10 at the tumor site, both of which are responsible for the enhanced efficacy of poly-ICLC-assisted vaccines.
In Specific Aim (SA)1, we will determine whether promotion of Type-1 phenotype is the critical factor for the efficacy of poly-ICLC assisted GAA vaccines. Findings from these studies will allow us to determine the critical surrogate markers in our clinical trial proposed in SA3. In collaboration with Project 1 and 3, in our SA2, we will evaluate our hypothesis that inhibition of STATS signals may improve the efficacy of poly-ICLC assisted GAA-based vaccines. In addition, enhanced local IFN expression by tumor-infiltrating effector cells, may induce Indoleamine 2,3 dioxygenase (IDO), which inhibits proliferation of both T cells and Herpes-Simplex Viruses (HSV). We will determine whether poly-ICLC-assisted GAA-vaccines can be efficiently combined with HSV-therapy under the inhibition of IDO in collaboration with Project 3. We will implement a phase I/I I trial of vaccinations with human GAA-peptides identified during the initial funding period in conjunction with poly-ICLC in participants with recurrent malignant glioma. These proposed studies will provide a strong basis for a near future development of effective combination therapeutic strategies using vaccination with signal transduction modulation and/or HSV therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS040923-09
Application #
8232995
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$244,258
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro Oncol 18:1157-68
Jane, Esther P; Premkumar, Daniel R; Cavaleri, Jonathon M et al. (2016) Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines. J Pharmacol Exp Ther 356:354-65
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study. J Neurooncol 130:517-527
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Mazzacurati, Lucia; Marzulli, Marco; Reinhart, Bonnie et al. (2015) Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther 23:99-107
Premkumar, Daniel R; Jane, Esther P; Pollack, Ian F (2015) Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells. Cancer Biol Ther 16:233-43
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
Foster, Kimberly A; Jane, Esther P; Premkumar, Daniel R et al. (2014) Co-administration of ABT-737 and SAHA induces apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines. J Neurooncol 120:459-72

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