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Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2008 Aug; Vol. 57 (8), pp. 1263-70. Date of Electronic Publication: 2008 Jan 31. - Publication Year :
- 2008
-
Abstract
- Promising anti-tumor responses have been observed in the clinic using monoclonal antibodies (mAbs) that block immune checkpoints. One concern with these therapeutic agents remains the potential induction of immune breakthrough events (IBEs) resulting from the disruption of T cell homeostasis or the breaking of tolerance to self antigens. As an approach to maintaining anti-tumor responses but decreasing the likelihood of these events, the local expression of a mAb in combination with a GM-CSF-secreting cancer immunotherapy was evaluated. Using anti-cytotoxic T lymphocyte antigen (CTLA)-4 as a model antibody to test this hypothesis, tumor cell lines were generated that expressed the full-length mAb in addition to GM-CSF. Evaluation of these cell lines in two therapeutic tumor models revealed that local, cell-mediated delivery of anti-CTLA-4 from a GM-CSF-secreting tumor cell immunotherapy activated potent anti-tumor responses and prolonged overall survival at significantly lower serum mAb levels in the host. Furthermore, lowering the systemic exposure of the host to the immune modulatory mAb correlated with reduced evidence of systemic autoimmunity. This approach has broad utility for the delivery of mAbs or proteins locally from cellular immunotherapies to minimize IBEs while retaining the potent therapeutic effects of such combination treatments.
- Subjects :
- Animals
Antibodies, Monoclonal genetics
CTLA-4 Antigen
Cell Line, Tumor
Cloning, Molecular
Disease Models, Animal
Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Hybridomas immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Transplantation
Neoplasms, Experimental metabolism
Recombinant Proteins biosynthesis
Recombinant Proteins genetics
Recombinant Proteins metabolism
Antibodies, Monoclonal biosynthesis
Antigens, CD immunology
Autoimmunity immunology
Immunotherapy
Neoplasms, Experimental immunology
Neoplasms, Experimental therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0340-7004
- Volume :
- 57
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 18236040
- Full Text :
- https://doi.org/10.1007/s00262-008-0451-3