Intratumorally anchored cytokine therapy.

Introduction: On-target, off-tumor toxicity severely limits systemic dosing of cytokines and agonist antibodies for cancer. Intratumoral administration is increasingly being explored to mitigate this problem. Full exploitation of this mode of administration must include a mechanism for sustained retention of the drug; otherwise, rapid diffusion out of the tumor eliminates any advantage.

Areas Covered: We focus here on strategies for anchoring immune agonists in accessible formats. Such anchoring may utilize extracellular matrix components, cell surface receptor targets, or exogenously administered particulate materials. Promising alternative strategies not reviewed here include slow release from the interior of a material depot, expression following local transfection, and conditional proteolytic activation of masked molecules.

Expert Opinion: An effective mechanism for tissue retention is a critical component of intratumorally anchored cytokine therapy, as leakage leads to decreased tumor drug exposure and increased systemic toxicity. Matching variable drug release kinetics with receptor-mediated cellular uptake is an intrinsic requirement for the alternative strategies mentioned above. Bioavailability of an anchored form of the administered drug is key to obviating this balancing act.