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. ? ? ?
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