Despite 20 years of clinical trials, systemically administered interleukin-2 (IL-2) induces clinical responses in only a very small minority of patients with only a few types of cancer. Based on the assumption that the results are limited largely by inadequate concentrations of IL-2 at the tumor sites and by the toxicity of high dose IL-2, approaches are being explored to deliver IL-2 preferentially or specifically to the tumor.
Carnemolla and colleagues (page 1659) have devised a novel delivery system, namely, a fusion protein between IL-2 and a human antibody (L19) directed against an extracellular matrix (ECM) component of newly forming tumor blood vessels. In this study, the fusion protein (L19–IL-2) administered to tumor-bearing mice selectively delivered IL-2 to the tumor vessels and exerted a significant antitumor effect. The localization to the tumor vessels suggests applicability to “solid” tumors, and even to hematologic malignancies, forming new blood vessels.
IL-2 is not directly cytotoxic and the mechanism for its antitumor effect—whether via T cells, NK cells, or other cytokines—differs for different cancers. Therefore, the clinical therapeutic effect of IL-2 delivered by L19–IL-2 might be restricted to those cancers known to respond to systemic IL-2 or the increased IL-2 concentration at the tumor site might exert an antitumor effect on cancers not known to respond to systemic IL-2. The former possibility would improve the therapeutic index, while the latter would represent a major advance in cancer therapy.
Angiogenesis-associated ECM components represent pan-tumor antigens, which can serve as targets for the delivery of a variety of immunostimulatory or cytotoxic molecules, for example, GM-CSF or IL-12, or toxins or radiation, for example, I131 or Y90, selectively to tumor sites for greater antitumor activity and less toxicity. This study represents one such exciting approach.