Current anticancer
therapy is a delicate balance between elimination of malignant cells and harmful side effects for the host. In this study, we used a
tumor-homing
peptide to engineer anti-CD40 agonist
antibodies and recombinant
IL-2 such that they were selectively delivered into spontaneously arising
tumors in a transgenic mouse model of islet cell
carcinogenesis.
Intravenous injection of these agents, either separately or together, led to accumulation in the vicinity of
tumor neovessels without toxic side effects. Although both molecules are critical for adaptive immunity, the most profound effects were seen in endothelial cells. Combined, local anti-CD40 and
IL-2 therapy reduced
tumor vascularity and significantly delayed
tumor growth in mice. Remarkably,
tumor-bearing mice remained disease-free long-term when targeted anti-CD40 and
IL-2 were combined with transfers of preactivated antitumor immune cells. In this therapeutic setting, triggering of CD40 on endothelial cells induced an inflammatory response of the vessel wall and facilitated effector cell accumulation in the
tumor parenchyma while
IL-2 promoted
antigen-specific immune cell persistence. We believe this is a novel and highly effective anticancer approach, whereby
tumor stroma is "conditioned" for enhanced immune cell entry and survival, facilitating immune-mediated
tumor destruction and leading to a sustained antitumor response.