Engineering a multi-targeted nanoparticle-based immunotherapy for pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with no durable treatment options for advanced stages, and, as such, has quickly risen to the 3rd leading cause of cancer-related death. Systemic cytotoxic and immunotherapy failure is largely due the desmoplastic and immune suppressive PDAC tumor microenvironment (TME) that limits drug penetrance and immune infiltration and activation. Indeed, poor tumor antigen presentation and suppression of both the innate and adaptive immune arms limit the efficacy of immune checkpoint blockade (ICB) therapies that can achieve durable tumor responses in other advanced solid tumors. Thus, there is an urgent need for novel drug delivery and therapy combinations to overcome multiple immune suppressive barriers in PDAC and harness the immune system to eradicate this lethal malignancy. The Ruscetti and Atukorale labs have recently collaborated to show that systemic delivery of a combination of (a) the RAS pathway inhibitors trametinib and palbociclib (T/P) in free form and (b) STING/TLR4 innate immune agonists encapsulated into lipid nanoparticles (NPs) synergistically enhances antigen presentation by tumor cells and dendritic cells (DCs) as well as CD8+ T cell infiltration and cytotoxicity, leading to type I interferon (IFN)- dependent anti-tumor immune control in preclinical PDAC models. Here we will leverage versatile lipid-based chemistries to engineer T/P or RAS inhibitor RMC-7977 and STING/TLR4 agonists into “targeted” NPs to home them specifically to tumor cells and DCs, respectively, in the PDAC TME to enhance on-target specificity and reduce toxicity. We hypothesize that agonist-NPs co-administered with inhibitor-NPs will drive a safe and coordinated innate and adaptive anti-tumor immune response in the PDAC TME to overcome immunosuppression and potentiate ICB efficacy to achieve long-term PDAC tumor control. This proposal takes advantage of expertise and tools from the Atukorale lab in nanotechnology engineering and innate immune agonism, the Ruscetti, Lewis, and Brehm labs in pancreatic cancer immune suppression, mouse models, and RAS targeted therapy strategies, and the Fitzgerald lab in mechanisms of IFN signaling to develop a novel immunotherapy platform for PDAC. In Aim 1, we will engineer NP targeting of agonists and inhibitors to optimize their tumor biodistribution, inflammatory signaling, and safety and efficacy in PDAC mouse models. In Aim 2, we will investigate the effects of NP therapy combinations on local and systemic immune responses, and determine the role of IFN signaling in DCs in driving anti-tumor immunity. In Aim 3, we will evaluate the impact of agonist and inhibitor-NP therapy on T cell activation and exhaustion, and whether these therapies combine effectively with anti-PD-1 ICB to potentiate long-lasting cytotoxic T cell immunity in mouse and human preclinical PDAC models. Overall, this project has the potential to uncover novel (a) engineering approaches to overcome drug delivery issues in PDAC, (b) inflammatory signaling mechanisms to target innate and adaptive immune suppression, and (c) multi-targeted immunotherapy regimens to immunologically treat PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer arises within an immune suppressive tumor microenvironment that limits anti-tumor immunity, drug delivery, and the efficacy of immune checkpoint blockade (ICB) therapy that has demonstrated remarkable success in other cancer types. We have recently shown that combinations of RAS pathway inhibitors targeting oncogenic signaling in pancreatic tumors and innate immune agonists loaded into nanoparticles (NPs) can synergistically target multiple mechanisms of immune suppression and activate cytotoxic T cell immunity in PDAC. This proposal aims to engineer tumor and immune targeting therapies in NPs to specifically deliver them to the PDAC microenvironment with minimal toxicity and evaluate their impact on anti-tumor immune responses and ICB outcomes, with the goal of developing a novel immunotherapy regimen for lethal pancreatic cancer that still remains without effective treatment options.