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Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
Cancer Immunol Immunother. 2013 Aug; 62(8):1369-80.CI

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.

Authors+Show Affiliations

Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23715927

Citation

Hornig, Nora, et al. "Evaluating Combinations of Costimulatory Antibody-ligand Fusion Proteins for Targeted Cancer Immunotherapy." Cancer Immunology, Immunotherapy : CII, vol. 62, no. 8, 2013, pp. 1369-80.
Hornig N, Reinhardt K, Kermer V, et al. Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. Cancer Immunol Immunother. 2013;62(8):1369-80.
Hornig, N., Reinhardt, K., Kermer, V., Kontermann, R. E., & Müller, D. (2013). Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. Cancer Immunology, Immunotherapy : CII, 62(8), 1369-80. https://doi.org/10.1007/s00262-013-1441-7
Hornig N, et al. Evaluating Combinations of Costimulatory Antibody-ligand Fusion Proteins for Targeted Cancer Immunotherapy. Cancer Immunol Immunother. 2013;62(8):1369-80. PubMed PMID: 23715927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. AU - Hornig,Nora, AU - Reinhardt,Katharina, AU - Kermer,Vanessa, AU - Kontermann,Roland E, AU - Müller,Dafne, Y1 - 2013/05/30/ PY - 2013/03/14/received PY - 2013/05/17/accepted PY - 2013/5/30/entrez PY - 2013/5/30/pubmed PY - 2013/11/5/medline SP - 1369 EP - 80 JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol. Immunother. VL - 62 IS - 8 N2 - 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. SN - 1432-0851 UR - https://www.unboundmedicine.com/medline/citation/23715927/Evaluating_combinations_of_costimulatory_antibody_ligand_fusion_proteins_for_targeted_cancer_immunotherapy_ L2 - https://dx.doi.org/10.1007/s00262-013-1441-7 DB - PRIME DP - Unbound Medicine ER -