Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models
Autor: | Jonathan Rios-Doria, Jon Chesebrough, Robert E. Hollingsworth, Nicholas Holoweckyj, Nicholas M. Durham, Wei Zhao, Raymond Rothstein, Ching Ching Leow, Leslie Wetzel |
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Jazyk: | angličtina |
Předmět: |
Cancer Research
medicine.medical_treatment Mice Nude Biology Pharmacology lcsh:RC254-282 Article Polyethylene Glycols Immune system In vivo Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Animals Doxorubicin Mice Inbred BALB C Antibiotics Antineoplastic Cancer Antibodies Monoclonal Drug Synergism Immunotherapy lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Survival Analysis Tumor Burden Mice Inbred C57BL Disease Models Animal Treatment Outcome Immunogenic cell death Female CD80 CD8 Algorithms medicine.drug |
Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 17, Iss 8, Pp 661-670 (2015) |
ISSN: | 1476-5586 |
DOI: | 10.1016/j.neo.2015.08.004 |
Popis: | Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity. |
Databáze: | OpenAIRE |
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