Strategies for improving the anti-neoplastic activity of TNF by tumor targeting

The clinical use of tumor necrosis factor (TNF) as an anticancer drug has been so far limited to loco-regional treatments because of severe dose-limiting toxicity. This chapter intends to review the targeting approaches and the animal models that have been developed in an attempt to improve the therapeutic activity of this cytokine and to enable systemic administration of a therapeutic dose. Using various animal models, evidence was obtained to suggest that the targeting approach could indeed improve the therapeutic properties of this cytokine, either alone or in combination with chemotherapy. Targeted delivery of TNF can be achieved by targeting tumor cell antigens, directly or indirectly by a pretargeting approach, or by targeting antigens expressed within tumor vessels. In both cases the mechanism of the improved antitumor activity appears to be related to indirect effects of TNF on tumor-associated vessels. Thus, targeting markers that are selectively expressed or upregulated in angiogenic tumor vessels seems to be the best choice for developing TNF conjugates with improved activity.