TARGETING THE VASCULATURE OF SOLID TUMORS

Immunotoxins and other antibody-based therapeutic reagents have proved effective against lymphomas and leukemias but results with carcinomas and other solid tumors have thus far proved disappointing. A major reason for this difference is that solid tumors are relatively impermeable to macromolecules. A solution to this problem would be to attack the endothelial cells of the tumor vascular bed rather than the tumor cells themselves. We have developed a mouse model of this 'vascular targeting' approach where genetic modification of the tumor cells causes them to induce the expression of an experimental marker (MHC Class II) on tumor endothelium. In this report we show that an anti-Class II-deglycosylated Ricin A-chain immunotoxin kills activated endothelial cells in tissue culture and, when injected into appropriate tumor-bearing mice, causes complete thrombosis of the tumor vasculature and dramatic regressions of large solid tumors. These findings suggest that therapeutic agents derived from recently-described antibodies against human tumor endothelium could provide a general treatment for disseminated solid cancers in man.