期刊
MOLECULAR THERAPY
卷 26, 期 9, 页码 2243-2254出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2018.06.001
关键词
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资金
- European Commission Marie Curie Innovative Training Network (ITN) grant VIRION (H2020-MSCA-ITN-2014 project) [643130]
- Jane and Aatos Erkko Foundation
- HUCH Research Funds (EVO)
- Sigrid Juselius Foundation
- Finnish Cancer Organizations
- University of Helsinki
- TILT Biotherapeutics Ltd
- Marie Curie Actions (MSCA) [643130] Funding Source: Marie Curie Actions (MSCA)
Lymphodepleting preconditioning with high-dose chemotherapy is commonly used to increase the clinical efficacy of adoptive T cell therapy (ACT) strategies, however, with severe toxicity for patients. Conversely, oncolytic adenoviruses are safe and, when engineered to express interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-alpha), they can achieve antitumor immunomodulatory effects similar to lymphodepletion. Therefore, we compare the safety and efficacy of such adenoviruses with a cyclophosphamide-and fludarabine- containing lymphodepleting regimen in the setting of ACT. Human adenovirus (Ad5/3-E2F-D24-hTNF-alpha-IRES-hIL-2; TILT-123) replication was studied using a Syrian hamster pancreatic tumor model (HapT1) infused with tumor- infiltrating lymphocytes (TILs). Using the oncolytic virus instead of lymphodepletion resulted in superior efficacy and survival. Immune cells responsive to TNF-alpha IL-2 were studied using an immunocompetent mouse melanoma model (B16. OVA) infused with ovalbumin-specific T (OT-I) cells. Here, the adenovirus approach improved tumor control together with increased intratumoral Th1 cytokine levels and infiltration of CD8+ T cells and CD86+ dendritic cells. Similar to humans, lymphodepleting preconditioning caused severe cytopenias, systemic inflammation, and damage to vital organs. Toxicity was minimal in adenovirus- and OT-Itreated mice. These findings demonstrate that ACT can be effectively facilitated by cytokine-coding adenovirus without requiring lymphodepletion, a rationale being clinically investigated.
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