Mendez-Gomez et al. showed that multi-lamellar tumor- and model-antigen RNA lipid particle aggregates (RNA-LPAs), delivered i.v., transfected fibroblastic stroma cells to activate cytosolic pattern recognition receptors to induce cytokines/chemokines, DC/lymphocyte migration, peripheral/intratumoral specific primary and recall responses, and tumor rejection in murine models. Tumor-derived RNA-LPA infusions in client-owned canines with terminal spontaneous gliomas were well tolerated, rapidly induced an immunologically “hot” TMEs, and improved survival outcomes. In a first-in-human glioblastoma trial, RNA-LPA infusions rapidly induced immune activation in the periphery and TME, and glioma antigen-specific responses.
Contributed by Paula Hochman
ABSTRACT: Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
Author Info: (1) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (2) University of Florida L
Author Info: (1) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (2) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (3) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (4) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (5) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida Genetics Institute, Gainesville, FL 32610, USA. (6) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (7) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (8) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (9) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (10) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (11) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (12) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (13) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (14) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (15) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (16) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (17) University of Texas at Austin, College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Austin TX 78712. (18) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (19) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (20) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (21) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (22) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (23) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (24) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (25) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (26) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (27) University of Florida, Division of Quantitative Sciences, UF Health Cancer Center, Gainesville, FL 32610, USA. (28) University of Florida, College of Veterinary Medicine, Gainesville, FL 32610, USA. (29) University of Florida, Department of Medicine, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (30) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (31) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (32) University of Florida, College of Veterinary Medicine, Gainesville, FL 32610, USA. (33) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. (34) University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. (35) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (36) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (37) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (38) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (39) University of California, San Francisco, Department of Neurological Surgery, San Francisco, CA 94158, USA. (40) University of Texas at Austin, College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Austin TX 78712. (41) University of Florida Interdisciplinary Center for Biotechnology Research, Gainesville, FL 32610, USA. (42) University of Florida Interdisciplinary Center for Biotechnology Research, Gainesville, FL 32610, USA. (43) University of Florida, Department of Biostatistics, Gainesville, FL 32610, USA. (44) University of Florida, Department of Radiology, Gainesville, FL 32610, USA. (45) University of Florida, Department of Pathology, Gainesville, FL 32610, USA. (46) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (47) Children's National Hospital, Center for Cancer and Blood Disorders, Washington, DC 20010, USA. (48) University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Department of Pediatrics, Division of Oncology, Philadelphia, PA 19104, USA. (49) University of Florida, College of Veterinary Medicine, Gainesville, FL 32610, USA. (50) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (51) University of Florida, Department of Anesthesiology, Gainesville, FL 32610, USA. (52) University of California, San Francisco, Department of Neurology, Neurological Surgery, and Pediatrics, San Francisco, CA 94158, USA. (53) University of California, San Francisco, Department of Neurological Surgery, San Francisco, CA 94158, USA. (54) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (55) Cleveland Clinic, Center of Immunotherapy and Precision Immuno-Oncology/Head and Neck Institute, Cleveland, OH 44106, USA. (56) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA. (57) University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA. Electronic address: elias.sayour@neurosurgery.ufl.edu.
