Precision UCART and Nanoparticle Combination to Combat Hostile Microenvironments (PUNCH)

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is among the deadliest cancers and remains largely unresponsive to immunotherapy, including Chimeric Antigen Receptor T (CART) cell therapy, This project aims to develop a novel, multi-component immunotherapy platform that overcomes the complex immunesuppressive tumor microenvironment (TME) and expands patient accessibility through an off-the-shelf universal CART (UCART) system, The proposed strategy integrates UCART cells and intratumoral delivery of ID01 inhibitor prodrug-tethered lipid nanoparticles (pLNPs) encoding immune-modulatory mRNAs, The long-term objective is to develop a first-in-class, tunable combination therapy that addresses the unique challenges posed by metastatic PDA Specific aims: (1) Perform mechanistic studies comparing an off-the-shelf UCART platform to a conventional autologous (CART) platform to select a lead therapeutic chassis, (2) Define an optimal LNP-mRNA payload to enhance CART activity by remodeling the TME, (3) Determine whether adaptive resistance to CARTs in PDA can be overcome via delivery of an ID01 inhibitor via a pLNP, Each component will be assessed using 3D tumor spheroid models and orthotopic syngeneic or xenograft mouse models of PDA The project will determine the optimal approach to enhancing CART therapy of PDA via a combination with an LNP system that delivers TME-modulatory mRNAs and an ID01-inhibitor prod rug, The expected outcome is a preclinical proof-of-concept for a potent, modular therapy targeting PDA through synergistic TME reprogramming and off-the-shelf UCART cells, This approach addresses major gaps in the immunotherapy of PDA and supports the NCl's mission to lead, conduct, and support cancer research across the nation to advance scientific knowledge and help all people live longer, healthier lives.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Metastatic pancreatic cancer resists existing therapies and often progresses too rapidly for patients to be treated with autologous CART cell therapy, This project develops a novel, off-the-shelf CART cell therapy combined with a tumor-targeted lipid nanoparticle system that delivers therapeutic mRNAs and a conjugated immune checkpoint inhibitor, designed to overcome tumor-intrinsic and adaptive resistance mechanisms, Together, these components form a synergistic immunotherapy platform with the potential to transform outcomes for patients with metastatic pancreatic cancer.