Year: 2026
Type: conference-abstract
Abstract: Background Metastatic osteosarcoma (OSA) has a dismal prognosis despite novel targeted therapies, including CAR T-cells. Unleashing CAR T-cell therapy against poorly immunogenic cancers necessitates new technologies that modulate the tumor microenvironment (TME), while inducing CAR T-cell migration, proliferation, and persistence in the tumor to sustain tumor-specific immunity. To mitigate the clinical challenges of immunologically inert tumors, we designed an mRNA-lipid-particle (RNA-LPA) delivery system that encapsulates antigen-encoding or nonspecific mRNA with cationic lipids to generate multi-lamellar RNA-lipid nanoparticle aggregates (BB-IND #19304, Sayour). 1 We have adapted these as CD70-encoding RNA-LPAs to take advantage of the CD27-CD70 co-stimulatory immune axis and overcome CD70-specific CAR T-cell limitations in OSA.Methods Using two immunocompetent murine solid tumor models (K7M2 osteosarcoma in Balb/c mice and B16F0 melanoma in C57BL/6J mice) metastatic to lungs, we implanted K7M2 and B16F0 intravenously (i.v.), n = 8–12 mice/group. We subsequently generated LPAs complexed with RNA encoding for CD70-antigen and control vaccine (green fluorescent protein, GFP). RNA-LPAs were first administered intravenously on day 5 post-tumor implantation, followed by 3 weekly vaccines. Murine CD70-directed CAR T-cells were manufactured following activation of T-cells with CD3 and CD28 antibodies for 2 days. CAR T-cells were ready for use in downstream experiments 2 days post-CAR transduction and cells were injected (i.v.) 24 hours post-RNA-LPAs injection.Results Intravenous delivery of CD70-encoding RNA-LPAs rapidly recruit CD70-directed CAR T-cells into tumor sites. Regression of CD70-expressing murine tumors associates with CAR T-cell mobilization out of peripheral blood and into reticuloendothelial (RES) tissues (i.e. spleen) and tumor sites (i.e. lung), a phenomenon that correlates with upregulation of vaccine-induced type I interferons (IFN) and activation of CXCR3 pathway. In addition to the CAR T-mediated antitumor killing, immunoassays detected upregulation of pro-inflammatory mediators from CAR T-cell activity in the presence of CD70-encoding RNA-LPAs. The long-term survival benefit (150 days) provided by this approach reached 70–80% in both models compared with 0–10% of control groups.Conclusions Tumor trafficking and persistence of CD70-directed CAR T-cells depend on a coordinated cytokine/chemokine signaling axis that can be orchestrated through intravenous RNA-LPA vaccination, which unlock activity in two aggressive lung metastatic tumor models. RNA-LPAs in combination with CAR T-cells prolong long-term survival of mice bearing these aggressive tumor models, suggesting a synergistic therapeutic outcome. Future studies include the evaluation of this approach in large animal models prior to translation into first-in-human clinical trials.Reference Mendez-Gomez HR, DeVries A, Castillo P, von Roemeling C, Qdaisat S, Stover BD, Xie C, Weidert F, Zhao C, Moor R, Liu R, Soni D, Ogando-Rivas E, Chardon-Robles J, McGuiness J, Zhang D, Chung MC, Marconi C, Michel S, Barpujari A, … Sayour EJ. RNA aggregates harness the danger response for potent cancer immunotherapy . Cell 2024;187(10):2521–2535.e21. https://doi.org/10.1016/j.cell.2024.04.003
Institutions: University of Florida Health, University of Florida
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225307110