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.

Sign in via your Institution