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Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice
Juliana Hamzah, … , Günter J. Hämmerling, Ruth Ganss
Juliana Hamzah, … , Günter J. Hämmerling, Ruth Ganss
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1691-1699. https://doi.org/10.1172/JCI33201.
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Research Article Oncology

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice

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Abstract

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.

Authors

Juliana Hamzah, Delia Nelson, Gerd Moldenhauer, Bernd Arnold, Günter J. Hämmerling, Ruth Ganss

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Figure 4

CD40 expression on tumor blood vessels.

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Adoptive T cell therapy in the presence of intratumoral inflammation.
(A...
(A) To display blood vessels, 27-week-old RIP1-Tag5 mice were i.v. injected with FITC-labelled tomato lectin. Tumors were harvested and stained with anti-CD40 antibodies. Equally strong CD40 signals were visible in tumor nodules of different sizes analyzed in RIP1-Tag5 mice at 23, 25, and 30 weeks of age (data not shown). (B) CD40 expression is not detectable by immunohistochemistry in normal pancreatic tissue. Dotted lines delineate islet of Langerhans. (C) CD40 expression on lectin-perfused tumor vessels from 27-week-old CD40–/–→RIP1-Tag5 (CD40–/–→RT5) mice and (D) absence of CD40 expression on the vasculature of 27-week-old C3H→RIP1-Tag5×CD40–/– mice displayed after anti-CD31 and anti-CD40 staining. Original magnification, ×40. Scale bar: 25 μm. (E) Survival analyses of chimeric RIP1-Tag5 mice and (F) chimeric RIP1-Tag5 mice after anti-CD40–RGR/IL-2–RGR combination treatment (n = 8; P = 0.004 and P = 0.03 compared with chimeric untreated controls).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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