Despite advances in surgery, chemo- and radiation-therapy, patients with glioblastoma multiforme (GBM) have a grim prognosis with less than 10% of patients surviving more than 5 years. Recent studies have shown potential of T and B-cell responses against GBM. However, existing technologies fail to elicit robust levels of anti-GBM immune responses with therapeutic efficacy. Therefore, there is a critical need for an alternative and effective strategy that can achieve strong T and B-cell responses against GBM. Our long-term research goal is to characterize the structure/function relationship governing immune activation with biomaterials. Our objective in this application is to understand how physicochemical properties of biomaterial-based vaccine platforms impact materials interactions with lymphoid tissues, with particular emphasis on (i) in vivo antigen (Ag) accumulation in lymph nodes, (ii) Ag presentation by antigen-presenting cells, and (iii) induction of cytotoxic CD8+ T lymphocyte (CTL) and antibody (Ab) responses against GBM. To that end, we have developed a novel lipid-based system, called interbilayer-crosslinked multilamellar vesicles (ICMVs). We show that ICMVs (1) efficiently transport Ag to local draining lymph nodes, (2) promote Ag presentation by antigen-presenting cells, (3) generate stronger CTL responses than other conventional adjuvants, including CpG in water-in-oil adjuvant, Montanide (arguably one of the strongest CTL adjuvant systems in clinical trials), and (4) exert potent therapeutic efficacy in murine tumor models, including intracranial GBM. Here, we will synthesize a series of new ICMVs with varying materials properties and determine the effects of biomaterials on immune activation and induction of CTL and Ab responses. We will evaluate their therapeutic efficacy in murine models of transplantable GBM as well as genetically induced GBM. We will also assess our strategy in combination with therapies designed to stimulate immune functions within GBM. Overall, these studies will improve our understanding of the biology-materials interfaces and may lead to new design principles for biomaterials engineered to elicit robust levels of immune responses, delay tumor growth, and prevent relapse. More broadly, the work proposed will address current technical limitations in vaccine technologies and potentially lead to a new treatment option for GBM patients.
The proposed research is relevant to public health because these studies will improve our understanding of the biology-materials interfaces and may lead to new design principles for biomaterials engineered to elicit robust levels of immune responses, thereby addressing current technical limitations in vaccine technologies.
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