Therapeutic vaccination against melanoma has yet to realize its clinical potential. Several phase III clinical trials assessing efficacy of vaccination against cancer-testis antigens, whole cell lysates, or cancer associated antigens failed to meet their therapeutic endpoints. This failure is due to lack of antigen-specific cytotoxic T lymphocyte proliferation after vaccination. It is known vaccine efficacy requires spatiotemporal draining of both antigen and adjuvant to lymph nodes for stimulating innate immunity as well as antigen presentation. Because of their size and physicochemical properties, nanoparticle vaccines enable precision delivery of both antigen and adjuvant to relevant cell types in the lymph node. However, sufficient amplification of intracellular danger signals can remain challenging. Recently, our laboratory has discovered an amphiphilic block copolymer, PEG-b-PC7A, which directly binds and activates the stimulator of interferon genes (STING). This innate immune receptor generally recognizes cytosolic DNA, processed by cyclic GMP-AMP Synthase (cGAS) to its natural ligand 2?3?- cyclic GMP-AMP (cGAMP). However, PEG-b-PC7A directly binds to STING in a cGAS-cGAMP-independent process, amplifying the secretion of type I interferons after phagocytosis by antigen presenting cells. We have shown vaccinating tumor-bearing mice with a PC7A polymeric micelle and tumor-associated antigen formulation will lead to tumor growth inhibition. While this polymer shows remarkable nanoparticle self-assembly, pH- responsiveness, endosomolytic, and STING activating properties, anti-tumor immune response can be refractory in immunosuppressive tumor models. Therefore, I will address this problem by incorporating additional immuno- modulatory components in our formulation. Particularly, low expression of inflammatory cytokines will be addressed. I will formulate PC7A nanoparticle with toll-like receptor (TLR) agonists to increase expression of cytokines in non-redundant manners. While the TLR and STING pathways both converge on expression of type I interferons, the differences in adaptor proteins and signaling pathways (e.g. NF-?B) can lead to significant changes in the kinetics of cytokines expression after vaccination by unique agonists. In this application I will screen and identify PC7A nanoparticles encapsulating TLR agonists for improved interferon stimulation, CTL generation, and anti-tumor immunity. I hypothesize the TLR-7 agonist, Imiquimod (R837), encapsulated PC7A nanoparticles will show improved anti-tumor immunity due to non-redundancy in TLR7/STING-IRF3/7-induced transcription of type I interferons. This application will show innovation by formulating a new class of synergetic TLR-STING agonist nanoparticles, and the proposal is suited for this project because of the remarkable properties of the PC7A polymeric nanoparticles.
Synergy between STING and TLR agonist cancer vaccines may provide a potent immune stimulus for generating a cytotoxic T lymphocyte response. In this proposal, I will investigate the effects of durable and robust STING activation on the antigen presenting cells which engulf these nanoparticles. Particularly, I will optimize the innate stimulation of novel cancer vaccines for antigen-specific CTL generation and anti-tumor therapeutic response.
