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Local Delivery of Ox40l , Cd80 , and Cd86 mRNA Kindles Global Anticancer Immunity
Open accessPublished version of a preprint
Abstract
Localized expression of effector molecules can initiate antitumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic antitumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for costimulatory and immune-modulating factors. Intratumoral injection of the CART–mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local antitumor effect. Using a two-tumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic antitumor response, curing both tumors. The combination of Ox40l-, Cd80-, and Cd86-encoding mRNA resulted in the local upregulation of proinflammatory cytokines, robust local T-cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic antitumor immunity from a single localized injection. Significance: The mRNA-CART system is a highly effective delivery platform for delivering immunostimulatory genes into the tumor microenvironment for potential therapeutic development.
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“In addition, charge-altering releasable transporters162,247 and modified dendrimers248 can effectively deliver mRNA molecules in vitro and in vivo.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [162]
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Metadata
- Authors
- Haabeth, O. A. W., Blake, T. R., McKinlay, C. J., Tveita, A. A., Sallets, A., Waymouth, R. M., Wender, P. A., & Levy, R.
- Affiliations
- Oslo University Hospital (NO)
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- Levy, Ronald
- ORCID
- Venue
- Cancer Research
- Published
- 2019-04-01
- Volume
- 79
- Issue
- 7
- Pages
- 1624-1634
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6445668
- OpenAlex
- W2911764398
- Cited by
- 129
- References
- 48
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 18 · 2023: 21 · 2022: 20 · 2021: 22 · 2020: 12 · 2019: 8
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Funders
- HHS | National Institutes of HealthHHS | National Institutes of Health (NIH) (R35CA197353, NIH-CA031845)
- National Science FoundationNational Science Foundation (NSF) (NSF CHE-1607092, NSF CHE-848280)
- KreftforeningenKreftforeningen (Norwegian Cancer Society) (6918722)
- National Cancer CenterNational Cancer Center (T32 CA196585)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- systemic antitumor immunity, OX40L, CD80, CD86, costimulatory molecules, tumor microenvironment, tumor-infiltrating dendritic cells, tumor-infiltrating macrophages, T cell activation, draining lymph nodes, inflammatory cytokines
- MeSH terms
- Animals, Female, Membrane Glycoproteins, Mice, Inbred BALB C, Neoplasms, RNA, Messenger, B7-1 Antigen, Tumor Necrosis Factors, Mice, B7-2 Antigen, OX40 Ligand, Tumor Microenvironment
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