Antibody engineering, virus retargeting and cellular immunotherapy: one ring to rule them all?

Solid tumours present numerous obstacles for efficient systemic delivery of therapeutic agents. This goal has to face specific problems related to the nature of each targeting element, but also the physical barriers posed by tumours, such as heterogeneous blood supply and elevated interstitial pressure. These barriers impair the delivery to tumours of antibodies or viral particles. Immune cells are supposed to be endowed with the ability to target tumours, but in general, tumour cells themselves provide poor targets for immunological responses. A key challenge of tumour gene therapy (cell carrier- and/or viral vector-mediated) is to control the site at which genes are expressed by instructing cells or virus or to distinguish between target and non-target tissue. Thus, antibody-directed targeting of virus or cells could potentially improve both the safety and the efficacy of therapeutic gene delivery to tumours. Furthermore, virus production can rely on carrier cells under the transcriptional control of a factor activated after specific triggering of a tumour-specific receptor. Given that any of these anti-tumour strategies by themselves have fulfilled their therapeutic potential, we propose here their combination for developing more effective anti-cancer therapies.