1. CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging
- Author
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Iulia Diaconu, Vincenzo Cerullo, A. Karttunen, Markus Vähä-Koskela, Marko Ahonen, Suvi Parviainen, Mari Hirvinen, Akseli Hemminki, Parviainen, S., Ahonen, M., Diaconu, I., Hirvinen, M., Karttunen, A., Vähä-Koskela, M., Hemminki, A., and Cerullo, V.
- Subjects
Xenograft Model Antitumor Assay ,medicine.medical_treatment ,CD40 Ligand ,Genetic Vectors ,Oncolytic Viruse ,Antineoplastic Agents ,Apoptosis ,Biology ,Virus ,Antineoplastic Agent ,Mice ,chemistry.chemical_compound ,Immune system ,Genes, Reporter ,Cell Line, Tumor ,Tumor Microenvironment ,Genetics ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Molecular Biology ,Oncolytic Virotherapy ,Tumor microenvironment ,Oncolytic vaccinia viru ,Animal ,Apoptosi ,Neoplasms, Experimental ,Immunotherapy ,Th1 Cells ,Xenograft Model Antitumor Assays ,Virology ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,Th1 Cell ,Urinary Bladder Neoplasms ,chemistry ,Urinary Bladder Neoplasm ,Molecular Medicine ,Genetic Vector ,Vaccinia ,Human - Abstract
Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.
- Published
- 2013