Abstract |
Blockade of CTLA-4 by monoclonal antibodies (mAb) can mediate regression of tumors and increase the efficacy of tumor antigen specific vaccines. Blockade of CTLA-4 has also been shown to significantly increase the avidity of antigen-specific T cells after immunization with live recombinant viral vector based vaccine. Here, we demonstrate a biological synergy between CTLA-4 blockade and active vaccine therapy consisting of recombinant vaccinia and avipox viruses expressing carcinoembryonic antigen (CEA) and three T cell costimulatory molecules to enhance antitumor effects. However, this synergy was very much dependent on the temporal relationship of scheduling of the two agents. We evaluated the strategies in both a foreign antigen model using beta-galactosidase as immunogen, and in a " self" antigen model using CEA as immunogen. For antitumor activity the model used consisted of mice transgenic for human CEA and a murine carcinoma cell line transfected with CEA. The enhanced antitumor activity after vaccine and CTLA-4 blockade did not result in any signs of autoimmunity. These studies form a rational basis for the use of vector-based vaccines with anti-CTLA-4 and demonstrate that both enhancement of positive costimulatory signals and inhibition of negative costimulatory signals can be simultaneously exploited. These studies also underscore the importance of " drug" scheduling in vaccine combination therapies.
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Authors | Mala Chakraborty, Jeffrey Schlom, James W Hodge |
Journal | Cancer immunology, immunotherapy : CII
(Cancer Immunol Immunother)
Vol. 56
Issue 9
Pg. 1471-84
(Sep 2007)
ISSN: 0340-7004 [Print] Germany |
PMID | 17318654
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Chemical References |
- Antibodies, Monoclonal
- Antigens, CD
- Antigens, Differentiation
- CTLA-4 Antigen
- CTLA4 protein, human
- Cancer Vaccines
- Ctla4 protein, mouse
- Recombinant Proteins
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Topics |
- Animals
- Antibodies, Monoclonal
(pharmacology)
- Antibody Affinity
- Antigens, CD
(drug effects)
- Antigens, Differentiation
(drug effects)
- CTLA-4 Antigen
- Cancer Vaccines
(pharmacology)
- Cell Line, Tumor
- Drug Synergism
- Female
- Humans
- Immunization
(methods)
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Neoplasms
(immunology, therapy)
- Recombinant Proteins
(genetics)
- T-Lymphocytes
(immunology)
- Vaccinia virus
(genetics)
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