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

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Santos , J M , Cervera-Carrascon , V , Havunen , R , Zafar , S , Siurala , M , Sorsa , S , Anttila , M , Kanerva , A & Hemminki , A 2018 , ' Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy ' , Molecular therapy , vol. 26 , no. 9 , pp. 2243-2254 . https://doi.org/10.1016/j.ymthe.2018.06.001

Title: Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy
Author: Santos, Joao Manuel; Cervera-Carrascon, Victor; Havunen, Riikka; Zafar, Sadia; Siurala, Mikko; Sorsa, Suvi; Anttila, Marjukka; Kanerva, Anna; Hemminki, Akseli
Contributor: University of Helsinki, University of Helsinki
University of Helsinki, Department of Oncology
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Department of Oncology
University of Helsinki, Department of Oncology
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2018-09-05
Language: eng
Number of pages: 12
Belongs to series: Molecular therapy
ISSN: 1525-0016
URI: http://hdl.handle.net/10138/259033
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-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.
Subject: METASTATIC MELANOMA
INFILTRATING LYMPHOCYTES
ONCOLYTIC ADENOVIRUSES
CANCER-IMMUNOTHERAPY
HEART-FAILURE
HYPERTENSION
EFFICACY
PROLIFERATION
INFLAMMATION
RECEPTORS
3111 Biomedicine
3122 Cancers
1184 Genetics, developmental biology, physiology
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