The treatment of cancer has been one of the earliest and most frequent applications of gene therapy in experimental medicine. However, this indication entails unique difficulties, especially in the case of solid tumors.
Pioneering strategies were aimed to reverse the malignant phenotype or to induce the death of cancer cells by transferring tumor-suppressor genes, inhibiting oncogenes or selectively expressing toxic genes.
Proof of principle has been generated in abundant pre-clinical models and in humans. However, clinical efficacy is hampered by the difficulty in delivering therapeutic genes to a significant proportion of cancer cells in solid tumors using the currently available vectors.
Therefore, current work aims to extend the effect to non-transduced cancer cells. This can be achieved by local or systemic expression of secreted proteins with the ability to block key pathways involved in angiogenesis, cell proliferation and invasion.
Recent advances in gene therapy vectors allow sustained expression of transgenes and make these strategies feasible in the clinic.
Another attractive option is the stimulation of immune reactions against cancer cells using gene transfer. In this case the therapeutic genes are antigens, cytokines or proteins capable of blocking the immunosuppressive microenvironment of tumors.
Adaptation of replication-competent ( oncolytic ) viruses as vectors for these genes combines the intrinsic immunogenicity of viruses, their capacity to amplify gene expression and their direct lytic effect on cancer cells.
In general, the ‘immunogene therapy strategies offer the opportunity to destroy primary and distant lesions, especially if they are combined with other treatments that reduce tumor burden.
More importantly, vaccination against cancer cells could prevent cancer relapse.
Finally, gene and cell therapies are joining forces to improve the efficacy of adoptive cell therapy. Ex vivo gene transfer of natural or chimeric tumor-specific receptors in T lymphocytes enhances the cytotoxic potency of the cells and is expanding the applicability of this promising approach to different tumor types. ( Xagena )
Hernandez R, Human Gene Therapy, 2013