Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice.
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.
Hamzah
Juliana
J
Western Australian Institute for Medical Research, University of Western Australia Centre for Medical Research, Perth, Western Australia, Australia.
Nelson
Delia
D
Moldenhauer
Gerd
G
Arnold
Bernd
B
Hämmerling
Günter J
GJ
Ganss
Ruth
R
D007516:Adenoma, Islet Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015996:Survival Rate; D016896:Treatment Outcome
D000906:Antibodies; D019013:CD40 Antigens; D020690:GTPase-Activating Proteins; D007376:Interleukin-2; D010455:Peptides; C490620:Ralbp1 protein, mouse; D011993:Recombinant Fusion Proteins