Cited by 129Immunotherapy and Immune ResponsesRNA Interference and Gene DeliveryCancer Immunotherapy and Biomarkers

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Local Delivery of Ox40l , Cd80 , and Cd86 mRNA Kindles Global Anticancer Immunity

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Haabeth, Ole Audun Werner, Blake, Timothy R., McKinlay, Colin J., Tveita, Anders A., Sallets, Adrienne, Waymouth, Robert M., Wender, Paul A., Levy, Ronald·2019·Cancer Research

DOI 10.1158/0008-5472.can-18-2867PMC PMC6445668

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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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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: Haabeth, Ole Audun Werner
Blake, Timothy R.
McKinlay, Colin J.
Tveita, Anders A.
Sallets, Adrienne
Waymouth, Robert M.
Wender, Paul A.
Levy, Ronald
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2019-04-01
Volume: 79
Issue: 7
Pages: 1624-1634
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-18-2867
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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Local Delivery of Ox40l , Cd80 , and Cd86 mRNA Kindles Global Anticancer Immunity

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