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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 3

Intratumoral anti-CD40/IL-2 treatment reduces tumor vascularity.

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Therapeutic efficacy of intratumoral anti-CD40/IL-2 treatment.
(A) Schem...
(A) Representative anti-CD31 vessel staining in 30-week-old RIP1-Tag5 tumors in anti-CD40–RGR/IL-2–RGR (left panel) or anti-CD40/IL-2 (right panel) treatment groups after 7 weeks of treatment and vessel counts. Vessel density was quantified by counting the number of CD31+ vessels within randomly selected fields (n = 5 mice; 5 fields per tumor; *P = 0.005 compared with control mice treated with IgG/RGR peptide). (B) Corresponding hypoxia stain (hypoxyprobe-1 kit; Chemicon) and quantification of hypoxic tumor areas in different treatment groups (n = 5; *P = 0.005 compared with control mice). (C) CD8+ T cells in anti–CD40-RGR/IL-2–RGR (left panel) or anti-CD40/IL-2 (right panel) treated tumors and quantification of CD8+ and CD4+ T cell infiltrates (n = 5; no statistically significant difference was observed between treatment groups). (D) Schematic representation of treatment with anti-CD4+ and anti-CD8+ depletion for a period of 5 weeks. (E) Survival analysis of anti-CD4+ and anti-CD8+ depleted RIP1-Tag5 mice (control) and RIP1-Tag5 mice treated with anti-CD40–RGR/IL-2–RGR combination therapy and depleting antibodies or IgG control (n = 8; P = 0.005). (F) Quantification of vessel density in depletion groups (n = 3 mice; 5 fields per tumor; *P = 0.005, **P = 0.005 compared with CD4+/CD8+ depleted control mice). Original magnification, ×10 (A); ×20 (B and C). Scale bar: 100 μm (A); 50 μm (B and C).

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

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