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Mol Ther. 2018 Sep 5;26(9):2243-2254. doi: 10.1016/j.ymthe.2018.06.001. Epub 2018 Jul 13.

Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy.

Author information

1
TILT Biotherapeutics Ltd., 00290 Helsinki, Finland; Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
2
Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
3
Pathology Unit, Finnish Food Safety Authority (EVIRA), 00790 Helsinki, Finland.
4
Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Hospital, 00290 Helsinki, Finland.
5
TILT Biotherapeutics Ltd., 00290 Helsinki, Finland; Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland. Electronic address: akseli.hemminki@helsinki.fi.

Abstract

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-α), 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-α-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-α 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-I-treated mice. These findings demonstrate that ACT can be effectively facilitated by cytokine-coding adenovirus without requiring lymphodepletion, a rationale being clinically investigated.

KEYWORDS:

TCR modified T cell therapy; TIL therapy; adoptive T cell therapy; chemotherapy; interleukin-2; lymphodepleting preconditioning; oncolytic adenovirus; tumor necrosis factor alpha

PMID:
30017877
PMCID:
PMC6127851
[Available on 2019-09-05]
DOI:
10.1016/j.ymthe.2018.06.001

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