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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 Article has an altmetric score of 6

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 5

Adoptive T cell therapy in the presence of intratumoral inflammation.

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CD40 expression on tumor blood vessels.
(A) To display blood vessels, 27...
(A) Survival analyses of RIP1-Tag5 mice treated with IL-2–RGR, anti-CD40–RGR, and anti-CD40–RGR/IL-2–RGR in combination with adoptive transfers of preactivated CD4+ and CD8+ Tag-specific T cells (T) (P values compared with IgG/RGR treated controls; Figure 2B). (B) Survival of RIP1-Tag5 mice treated with anti-CD40–RGR/IL-2–RGR and ConA activated lymphocytes from C3H mice (ConA T). (C) Kaplan-Meier analyses of chimeric RIP1-Tag5 mice receiving bone marrow from CD40 knockout (CD40–/–→RT5) or wild-type (C3H→RT5) mice and RIP1-Tag5 × CD40–/– receiving bone marrow from wild-type mice (C3H→RT5×CD40–/–), all treated with triple treatment (IL-2–RGR, anti-CD40–RGR, adoptive transfers of Tag-specific T cells) (n = 8–10 for all survival studies; P values compared with chimeric controls; Figure 4E). One of 2 experiments is shown. (D) RIP1-Tag5 mice at an age of 23 weeks were treated with 3 weekly injections of anti-CD40–RGR antibodies, IgG, or RGR-peptide. Tumors from control mice treated with IgG (upper panels) or RGR peptide alone (middle panels) do not show reactivity for ICAM, VCAM, or E-selectin. Anti-CD40–RGR treated RIP1-Tag5 mice show upregulation of ICAM, VCAM, and E-selectin on tumor vessels (lower panel). Original magnification, ×10. Scale bar: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 9 patents
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