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Evaluating combinations of costimulatory antibody–ligand fusion proteins for targeted cancer immunotherapy

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Abstract

Combinatory strategies are becoming of increasing interest in cancer immunotherapy. Costimulation by individual members of the immunoglobulin-like (Ig)- and TNF superfamily have already shown promising antitumor potential, thus prompting the exploration of their synergistic abilities in combinatorial approaches. Here, we pursued a targeted strategy with antibody-fusion proteins composed of a tumor-directed antibody and the extracellular domain of the costimulatory ligand B7.1, 4-1BBL, OX40L, GITRL or LIGHT, respectively. Costimulatory activity was assessed in an experimental setting where initial T cell activation was induced by a bispecific antibody (tumor-related antigen × CD3). Advantage of combined targeted costimulation was shown for either B7.1 or 4-1BBL with OX40L, GITRL, LIGHT and 4-1BBL in terms of T cell proliferation and IFN-γ release. Since encouraging results were obtained by the combination of B7.1 and 4-1BBL, we adapted the model system for a time-shift setting. Here, enhanced proliferation and granzyme B expression as well as reduced PD-1 expression on the T cell population demonstrated the benefit of costimulation-assisted restimulation. Finally, the antitumor potential of this combinatorial setting was confirmed in vivo in a lung metastasis mouse model. Thus, combinatorial approaches with costimulatory antibody–ligand fusion proteins seem a promising strategy to be further investigated for cancer immunotherapy.

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Abbreviations

GITRL:

Glucocorticoid-induced TNF receptor ligand

LIGHT:

Homologous to lymphotoxins, shows inducible expression and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes

TNFSF:

Tumor necrosis factor superfamily

mAb:

Monoclonal antibody

FAP:

Fibroblast activation protein

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Acknowledgments

This work was supported by a Grant from the Deutsche Krebshilfe (108743). We would like to thank Robert Lindner for technical support on the high‐performance liquid chromatography analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany

    Nora Hornig, Katharina Reinhardt, Vanessa Kermer, Roland E. Kontermann & Dafne Müller

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  1. Nora Hornig
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  2. Katharina Reinhardt
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  3. Vanessa Kermer
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  4. Roland E. Kontermann
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  5. Dafne Müller
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Correspondence to Dafne Müller.

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Hornig, N., Reinhardt, K., Kermer, V. et al. Evaluating combinations of costimulatory antibody–ligand fusion proteins for targeted cancer immunotherapy. Cancer Immunol Immunother 62, 1369–1380 (2013). https://doi.org/10.1007/s00262-013-1441-7

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  • DOI: https://doi.org/10.1007/s00262-013-1441-7

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