Targeted nanoparticle-mediated “cold”-to-“hot” reprogramming of the tumor microenvironment of high-risk neuroblastoma
This project seeks to develop a targeted nanoparticle therapy that harnesses proinflammatory innate immune cells to reprogram TME immunity in high-risk NB. Currently, survival for high-risk metastatic NB remains ~50% at 5 years, even with chemotherapy given at maximal tolerated dosing, which itself imparts debilitating long-term sequelae in >90% of survivors. The success of targeted immunotherapies for leukemias and lymphomas has not translated to pediatric solid tumors, which typically present as immunosuppressed “cold” tumors with microenvironments that limit antigen presentation and sustained activation of cytotoxic CD8+ T cells. To date, immune checkpoint inhibitor and CAR T approaches have focused only on augmenting CD8+ T cells, which are often rendered ineffective by the “cold” TME. This rationale highlights the critical need for harnessing innate APCs, such as DCs and macrophages, as key producers of “hot” proinflammatory cytokines for “cold”-to-“hot” TME reprogramming is gaining attention as a critical component in an effective T cell response. Our “cold”-to-“hot” reprogramming strategy is to deliver immuno-NPs that co-encapsulate synergistic STING and TLR4 innate immune agonists to the TME and promote the production of powerful Type I interferons upon NP uptake to activate APCs that prime and recruit CD8+ T cells. We will use a multi-targeted approach to harness multiple cell types to act in concert to bolster the APC response for robust long-term efficacy.
We hypothesize that innate immunoreactivity is a key missing link required for curative responses in solid tumors. The specific aims or research objectives of this proposal are to: first, identify accurate immuno-NP targeting schemes for optimal delivery to NB tumors, and second, establish an effective immuno-NP treatment regimen for elimination of NB primary tumors and metastasis. We also anticipate that our strategy to activate innate antigen presentation will synergize with other clinical approaches (i.e., checkpoint inhibition) to generate long-term anti-tumor immunity with curative responses. It is critical to develop less toxic, effective therapies for all children with high-risk neuroblastoma. We are uniquely qualified to pursue these aims based on our recent publications, additional preliminary data, and our complementary strengths from both bioengineering (Atukorale Laboratory) and translational perspectives (Shohet Laboratory). Besides being an effective stand-alone therapy, we expect that our non-genotoxic approach may also synergize with other immunotherapies under development. As such, our strategy has potentially significant therapeutic impact for NB and other cancers where overcoming barriers to innate immune activation may be essential for cure.