Translation of nanoparticles (NPs) into human clinical trials for patients with refractory cancers has lagged due to unknown biologic reactivities of novel NP designs. To overcome these limitations, simple well-characterized mRNA lipid-NPs have been developed as cancer immunotherapeutic vaccines. While the preponderance of RNA lipid-NPs encoding for tumor-associated antigens or neoepitopes have been designed to target lymphoid organs, they remain encumbered by the profound intratumoral and systemic immunosuppression that may stymie an activated T cell response. Herein, we show that systemic localization of untargeted tumor RNA (derived from whole transcriptome) encapsulated in lipid-NPs, with excess positive charge, primes the peripheral and intratumoral milieu for response to immunotherapy. In immunologically resistant tumor models, these RNA-NPs activate the preponderance of systemic and intratumoral myeloid cells (characterized by coexpression of PD-L1 and CD86). Addition of immune checkpoint inhibitors (ICIs) (to animals primed with RNA-NPs) augments peripheral/intratumoral PD-1(+)CD8(+) cells and mediates synergistic antitumor efficacy in settings where ICIs alone do not confer therapeutic benefit. These synergistic effects are mediated by type I interferon released from plasmacytoid dendritic cells (pDCs). In translational studies, personalized mRNA-NPs were safe and active in a client-owned canine with a spontaneous malignant glioma. In summary, we demonstrate widespread immune activation from tumor loaded RNA-NPs concomitant with inducible PD-L1 expression that can be therapeutically exploited. While immunotherapy remains effective for only a subset of cancer patients, combination therapy with systemic immunomodulating RNA-NPs may broaden its therapeutic potency.
Author Info: (1) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Med
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Author Info: (1) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (2) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (3) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (4) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (5) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (6) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (7) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (8) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (9) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (10) Department of Pathology, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (11) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. Department of Neuroscience, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (12) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (13) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (14) Department of Infectious Disease, College of Veterinary Medicine , University of Florida , Gainesville , Florida 32611 , United States. (15) Department of Small Animal Clinical Sciences, College of Veterinary Medicine , University of Florida , Gainesville , Florida 32611 , United States. (16) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States. (17) Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Lillian S. Wells Department of Neurosurgery, College of Medicine , University of Florida , Gainesville , Florida 32611 , United States.
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