Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity Journal Article
| Authors: | Simmons, A. D.; Moskalenko, M.; Creson, J.; Fang, J.; Yi, S.; VanRoey, M. J.; Allison, J. P.; Jooss, K. |
| Article Title: | Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity |
| 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. © 2008 Springer-Verlag. |
| Keywords: | controlled study; overall survival; drug efficacy; nonhuman; drug megadose; animal cell; mouse; animals; mice; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; low drug dose; melanoma; granulocyte macrophage colony stimulating factor; animal experiment; animal model; antineoplastic activity; drug potency; cell line, tumor; mice, inbred balb c; mice, inbred c57bl; cloning, molecular; antibodies, monoclonal; immunotherapy; recombinant antibody; recombinant proteins; tumor cell line; neoplasms, experimental; autoimmunity; immunomodulation; local; antigens, cd; neoplasm transplantation; disease models, animal; cytokine release; colon adenocarcinoma; antibody; gm-csf; granulocyte-macrophage colony-stimulating factor; antibody blood level; passive immunization; anti-ctla-4; hybridomas |
| Journal Title: | Cancer Immunology, Immunotherapy |
| Volume: | 57 |
| Issue: | 8 |
| ISSN: | 0340-7004 |
| Publisher: | Springer |
| Date Published: | 2008-08-01 |
| Start Page: | 1263 |
| End Page: | 1270 |
| Language: | English |
| DOI: | 10.1007/s00262-008-0451-3 |
| PUBMED: | 18236040 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 11" - "Export Date: 17 November 2011" - "CODEN: CIIMD" - "Source: Scopus" |
