The long term goal of Project 2 is to develop safe and effective immunotherapy strategies for CNS tumorsincorporating multi-disciplinary approaches that are being pursued in Projects 1 and 3. Despite the feasibilityand safety of cancer vaccine-approaches, current evidence suggests that the systemic induction of anti-tumorimmune responses by peripheral vaccines should be combined with modalities that enhance the homing andfunction of vaccine-induced effector cells within CNS tumor sites. Indeed, our studies from the prior fundingperiod have indicated that genetic delivery of interferon (IFN)-alpha into CNS tumors facilitates thetumor-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 moreclinically 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-lysineand carboxymethylcellulose (poly-ICLC). Our preliminary studies with the GL261 glioma model havedemonstrated that intramuscular (i.m.) administration of poly-ICLC improves the therapeutic effect ofvaccinations with GL261-derived glioma-associated antigen (GAA) CTL epitopes by enhancing the homing ofIFN-gamma expressing antigen-specific CTLs to the CNS tumor site. Based on the property of poly-ICLC toinduce IFNs as well as IP-10, we hypothesize that administration of poly-ICLC effectively induces Type-1GAA-specific effector cells as well as IP-10 at the tumor site, both of which are responsible for the enhancedefficacy of poly-ICLC-assisted vaccines.
In Specific Aim (SA)1, we will determine whether promotion of Type-1phenotype is the critical factor for the efficacy of poly-ICLC assisted GAA vaccines. Findings from thesestudies 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 STATSsignals may improve the efficacy of poly-ICLC assisted GAA-based vaccines. In addition, enhanced local IFNexpression by tumor-infiltrating effector cells, may induce Indoleamine 2,3 dioxygenase (IDO), which inhibitsproliferation of both T cells and Herpes-Simplex Viruses (HSV). We will determine whether poly-ICLC-assistedGAA-vaccines can be efficiently combined with HSV-therapy under the inhibition of IDO in collaboration withProject 3. We will implement a phase I/I I trial of vaccinations with human GAA-peptides identified during theinitial funding period in conjunction with poly-ICLC in participants with recurrent malignant glioma. Theseproposed studies will provide a strong basis for a near future development of effective combination therapeuticstrategies using vaccination with signal transduction modulation and/or HSV therapy.
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