Cells as Vehicles for Cancer Gene Therapy: The Missing Link Between Targeted Vectors and Systemic Delivery?

Abstract

Systemic administration of currently manufactured viral stocks has not so far achieved sufficient circulating titers to allow therapeutic targeting of metastatic disease. This is due to low initial viral titers, immune inactivation, nonspecific adhesion, and loss of particles. One way to exploit the elegant molecular manipulations that have been made to increase vector targeting is to protect these vectors until they reach the local sites of tumor growth. Various cell types home preferentially to tumors and can be loaded with the constructs required to produce targeted vectors. Here we discuss the potential of using such cell carriers to chaperone precious vectors directly to the tumors. The vectors can incorporate mechanisms to achieve tumor site-inducible expression, along with tumor cell-specific expression of the therapeutic gene and/or replicating viral genomes that would be released at the tumor. In this way, the great advances that have so far been made with the engineering of vector tropisms might be genuinely exploited and converted into clinical benefit.

Systemic inhibition of tumour angiogenesis by endothelial cell-based gene therapy

“…Our findings provide a rationale for developing antiangiogenic BOECs as an approach to gene therapy-mediated cancer treatment. Other gene therapies utilise viral or non-viral delivery systems, and the main drawback of these strategies is the absence of long-term expression of therapeutic proteins due to the probable immune response by the host to foreign material (Harrington et al, 2002). Early attempts to overcome these drawbacks involved delivery of genes to tumour sites via cell-based carriers.…”

Engineering mesenchymal stem cells for immunotherapy

“…MSCs are easily transduced by retroviral vectors, with a gene transfer efficacy between 50 and 85%. 37 This allowed long-term transgene expression, above 3 months in rodent models. MSCs may also be used as a vehicle to express cytokines and they have been efficiently transduced to secrete several therapeutic proteins such as human erythropoietin (EPO) or factor IX and in vivo, secretion was detected for up to 90 days following subcutaneous cell implantation.…”

Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies

“…11 Besides choice of delivery route, other strategies to evade or overcome the inhibitory effects of pre-existing antiviral antibodies can include surface modifications to mask the coat protein of viruses (eg polymer, polyethylene glycol) and use of cell carriers. [12][13][14][15] Cells have served as 'Trojan horses' to deliver viruses, as virus production 'factories' nested in tumors, and to potentially protect viruses from neutralizing antibodies, although no studies have yet evaluated antitumor efficacy using cell carriers in the presence of pre-existing antiviral antibodies in vivo. 14,[16][17][18][19][20][21][22][23] In this study, we explored the potential of using activated T cells as carriers for delivery of oncolytic MV to tumor sites.…”