Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer

Chemotherapy has been combined with therapeutic tumor-specific vaccination in an attempt to simultaneously debulk tumors, increase the effector lymphocyte:tumor cell ratio, and favor immune-mediated tumor rejection. However, chemotherapy is often inadequate because of insufficient and uneven drug penetration into tumors, and because it might also cause, in some instances, undesirable side effects and immunosuppression. Here, we suggest a combined approach based on targeted alteration of the endothelial barrier function with vascular disrupting agents, such as tumor necrosis factor-alpha (TNF-alpha), before chemotherapy and tumor-specific vaccination. This approach has the potential to empower chemoimmunotherapeutic strategies by improving cytotoxic drug penetration into tumors while exploiting the proinflammatory and immunostimulating activities of TNF-alpha and active immunotherapy.