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 organization: University of Helsinki
Department of Oncology
Clinicum
Department of Obstetrics and Gynecology
HUS Comprehensive Cancer Center
Date: 2018-09-05
Language: eng
Number of pages: 12
Belongs to series: Molecular therapy
ISSN: 1525-0016
DOI: https://doi.org/10.1016/j.ymthe.2018.06.001
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
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion


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