Principle of CAST strategy

Abstract

This chapter describes the conceptual basis of a novel form of cancer therapy that we have developed, which uses structural components of the stroma of a tumor as an anchor and launchpad for disseminating chemotherapeutic agents within a tumor. It also utilizes a phenomenon called the Enhanced Permeability and Retention (EPR) effect, described in this chapter and elsewhere in this book, to localize and concentrate the effect of the therapy on the lesion and minimize damage to healthy organs. We refer to this combined strategy as cancer (CA) stroma (S) targeting (T), CAST therapy. The concept of CAST therapy is that stroma-targeting immunconjugates extravasate selectively from tumor vessels (but not from normal counterparts), due to the EPR effect, bind to the stroma to create a scaffold, from which sustained release of cytotoxic agents occurs and subsequently diffuse throughout the tumor tissue to damage both tumor cells and tumor vessels. Various anticancer agents, gene-delivery systems, and monoclonal antibody (mAb)-based therapies have been produced, based on the enhanced permeability and retention (EPR) effect, but the current combination of EPR with cancer stroma targeting for delivery of a drug is original and new. As one example to illustrate how we utilize the CAST concept, we present a version using an antibody to insoluble fibrin. We have reported that hemorrhage caused by cancer erosion can induce fibrin clot formation that creates a mass of insoluble fibrin (IF) in the tumor stroma. Along with that, Influx of fibroblasts and inflammatory cells into the tumor tissue also occurs. Consequently, most cancers possess a fibrin-rich stroma that hinders the distribution of macromolecules, including antibody-drug conjugates (ADCs). Therefore, the EPR effect is not clinically and efficiently functioning in such situations. We have developed an anti-IF mAb that does not react with fibrinogen or soluble fibrin and have successfully created and optimized anti-IF ADCs. An ADC is an anti-IF antibody conjugated with monomethyl auristatin E (MMAE), a potent microtubule inhibitor, via a Val-Leu-Lys linker that is severed specifically by plasmin (PLM). Free MMAE is only released when the IF- ADC is bound to the epitopes in the IF because plasmin is only active on IF and is neutralized by the innate a2-plasmin inhibitor circulating in the blood. Free MMAE may therefore easily reach cancer cells by diffusing through the stromal barrier. MMAE released from IF-ADC may also attack the tumor vascular endothelial cells resulting in tumor necrosis.