A Pan-Inhibitor of DASH Family Enzymes Induces Immune-mediated Regression of Murine Sarcoma and Is a Potent Adjuvant to Dendritic Cell Vaccination and Adoptive T-cell Therapy
| Autor: | Terry J. Fry, Jack H. Lai, Barry Jones, Iwona Woznica, Yuxin Liu, Najat Bouchkouj, Shannon M. Larabee, Haiying Qin, Crystal L. Mackall, Brynn B. Duncan, Steven L. Highfill, William W. Bachovchin, Wengen Wu, Youhua Li, Peng Zhao |
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| Rok vydání: | 2013 |
| Předmět: |
Boron Compounds
Cancer Research Adoptive cell transfer Myeloid T-Lymphocytes medicine.medical_treatment T cell Immunology Cancer Vaccines Article Cell therapy Mice Adjuvants Immunologic Cell Line Tumor Rhabdomyosarcoma medicine Animals Immunology and Allergy Pharmacology Dipeptidyl-Peptidase IV Inhibitors business.industry Dendritic Cells Dipeptides Dendritic cell Immunotherapy medicine.disease Adoptive Transfer Combined Modality Therapy Tumor Burden Mice Inbred C57BL medicine.anatomical_structure Female business Immunologic Memory Adjuvant |
| Zdroj: | Journal of Immunotherapy. 36:400-411 |
| ISSN: | 1524-9557 |
| Popis: | Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT. |
| Databáze: | OpenAIRE |
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