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Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2013 Aug; Vol. 62 (8), pp. 1369-80. Date of Electronic Publication: 2013 May 30. - Publication Year :
- 2013
-
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.
- Subjects :
- 4-1BB Ligand genetics
4-1BB Ligand immunology
Animals
Antibodies, Bispecific genetics
Antibodies, Bispecific immunology
B7-1 Antigen genetics
B7-1 Antigen immunology
Cell Line, Tumor
Cell Proliferation drug effects
Cells, Cultured
Drug Evaluation, Preclinical
Granzymes immunology
Granzymes metabolism
HEK293 Cells
Humans
Interferon-gamma immunology
Interferon-gamma metabolism
Ligands
Lung Neoplasms immunology
Lung Neoplasms secondary
Lung Neoplasms therapy
Mice
Mice, Inbred C57BL
Neoplasms, Experimental immunology
Neoplasms, Experimental pathology
Programmed Cell Death 1 Receptor immunology
Programmed Cell Death 1 Receptor metabolism
Recombinant Fusion Proteins immunology
Recombinant Fusion Proteins pharmacokinetics
T-Lymphocytes drug effects
T-Lymphocytes immunology
T-Lymphocytes metabolism
Treatment Outcome
Tumor Burden drug effects
Tumor Burden immunology
Immunotherapy methods
Neoplasms, Experimental therapy
Recombinant Fusion Proteins therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 62
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 23715927
- Full Text :
- https://doi.org/10.1007/s00262-013-1441-7