The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

Abstract

Effective control of pancreatic cancer has been hampered primarily by the lack of tumor specificity of current treatment modalities. The highly specific antibody-mediated delivery of therapeutic agents to the tumor microenvironment might overcome this problem. We therefore investigated the therapeutic efficacy of the targeted immunocytokine L19-Interleukin-2 (L19-IL2), consisting of the human single-chain Fv antibody L19, which is highly specific for the extradomain B (ED-B) of fibronectin, and the human cytokine IL-2, in pancreatic cancer. Therapeutic effects of L19-IL-2, IL-2, and gemcitabine on tumor growth and metastasis were evaluated in orthotopic mouse models for pancreatic cancer. Immunohistochemistry was done to define ED-B expression, tumor necrosis, apoptosis, proliferation, and invasion of macrophages and natural killer (NK) cells. NK cells were depleted by i.v. injection of an anti-asialo-GM-1 antibody. ED-B is selectively expressed in human pancreatic cancer and in primary tumors and metastases of the mouse models. L19-IL-2 therapy was clearly superior to untargeted IL-2 or gemcitabine and inhibited tumor growth and metastasis with remarkable long-term tumor control. Therapeutic effects were associated with the induction of extensive tumor necrosis and inhibition of tumor cell proliferation. Immunohistochemistry revealed an increase of macrophages and NK cells in the tumor tissue, suggesting immune-mediated mechanisms. The functional relevance of NK cells for the therapeutic effect of the targeted immunocytokine L19-IL-2 was confirmed by NK cell depletion, which completely abolished its antitumor efficacy. These preclinical results strongly encourage the initiation of clinical studies using L19-IL-2 in pancreatic cancer.