Targeted delivery of adenoviral vectors by cytotoxic T cells

• Published in: Blood Vol. 104; no. 8; pp. 2272 - 2280
• Main Authors: Yotnda, Patricia, Savoldo, Barbara, Charlet-Berguerand, Nicolas, Rooney, Cliona, Brenner, Malcolm
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.10.2004; The Americain Society of Hematology; American Society of Hematology
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Applied cell therapy and gene therapy; Biological and medical sciences; Cell Line; Gene Expression; Genetic Therapy - instrumentation; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - physiology; Herpesvirus 4, Human - physiology; Humans; Kinetics; Life Sciences; Medical sciences; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - virology; Time Factors; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Viral Proteins - genetics; Viral Proteins - metabolism; Human; Adenoviridae; Metastasis; Malignant tumor; Genetic transfer; Virus; Treatment; Animal; CD40 ligand; Transduction; Gene therapy; Cytotoxic T lymphocyte; Vector; Tumor cell
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-3803

Effective targeting of vectors to tumor cells that have metastasized to multiple different tissue sites remains a major challenge for gene therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been shown in animal models and in humans to be able to cross tissue barriers and traffic to tumor cells. However, their capacity to eliminate malignancy has been limited by tumor immune evasion strategies. We now use a model of Epstein-Barr virus–mediated malignancy to show that human CTLs themselves may be modified to release therapeutic vectors following engagement of their antigen-specific receptors and that these vectors will effectively transduce and destroy tumor targets. We generated EBV-specific CTLs that were transgenic for the adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand (CD40L) promoter. Following transduction with E1-deficient adenoviral vectors, these CTLs produced infectious virus when exposed to HLA-matched EBV-expressing targets, but not on exposure to major histocompatibility complex (MHC)–mismatched or otherwise irrelevant cells. This approach provides a means of delivering oncolytic/therapeutic vectors not only to locally accessible macroscopic tumors as is presently the case, but also to disseminated metastatic disease, while avoiding the risks associated with systemic administration of large doses of adenoviral vectors.