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Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB

Nature Medicine volume 8, pages 343–348 (2002)Cite this article

Abstract

Monoclonal antibodies against the T-cell activation molecule 4-1BB have been effective in the treatment of established mouse tumors. To create a vaccine that stimulates the immune system similarly to the efficacious monoclonal anti-4-1BB antibody, 1D8, we constructed a vector encoding cell-bound single-chain Fv fragments from 1D8. We transfected the vector into cells from the K1735 melanoma, selected because of its low immunogenicity and very low expression of major histocompatibility complex class I. The transfected cells induced a strong type 1 T-helper cell response, for which CD4+ but not CD8+ T lymphocytes were necessary and that involved natural killer cells. Vaccinated mice rejected established wild-type K1735 tumors growing as subcutaneous nodules or in the lung. An analogous approach may be effective against micrometastases in human patients, including tumors whose expression of major histocompatibility complex class I is very low.

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Figure 1: K1735-1D8 cells transplanted into C3H mice are rejected by a mechanism dependent on CD4+ T cells and NK cells.
Figure 2: Immunization with K1735-1D8 cells, but not with irradiated K1735-WT cells, protects against outgrowth of transplanted K1735-WT cells by a mechanism that has memory and specificity.
Figure 3: Therapy of established K1735-WT tumors using K1735-1D8 cells as immunogen.
Figure 4: Proliferation of splenocytes from K1735-1D8 immunized mice.
Figure 5: INF-γ secretion and cytotoxic activity.

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Acknowledgements

We thank D. Malins for reviewing the manuscript and R. Mittler for providing monoclonal antibody against CD8 for CD8 cell depletion. This work was supported by National Institutes of Health grants CA79490, CA90143, CA85780 and 1P50 CA83636. Z.Y. is a visiting research fellow from Shanghai International Joint Cancer Institute and was also supported from China by an International Exchange Award to Y. Guo from National Science Foundation, Department of Health of People's Liberation Army and Shanghai Commission of Science & Technology.

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  1. Pacific Northwest Research Institute, Seattle, Washington, USA

    Zhengmao Ye, Ingegerd Hellström, Martha Hayden-Ledbetter, Amber Dahlin, Jeffrey A. Ledbetter & Karl Erik Hellström

  2. International Cancer Institute, The Second Military Medical University, Shanghai, China

    Zhengmao Ye

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Correspondence to Karl Erik Hellström.

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Ye, Z., Hellström, I., Hayden-Ledbetter, M. et al. Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat Med 8, 343–348 (2002). https://doi.org/10.1038/nm0402-343

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