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Science 22 March 1996:
Vol. 271. no. 5256, pp. 1734 - 1736
DOI: 10.1126/science.271.5256.1734
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Reports

Enhancement of Antitumor Immunity by CTLA-4 Blockade

Dana R. Leach, Matthew F. Krummel, James P. Allison *

One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.

Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
* To whom correspondence should be addressed.


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Chronic Immune Activation Associated with Chronic Helminthic and Human Immunodeficiency Virus Infections: Role of Hyporesponsiveness and Anergy.
G. Borkow and Z. Bentwich (2004)
Clin. Microbiol. Rev. 17, 1012-1030
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Adoptive Transfer of Paternal Antigen-Hyporesponsive T Cells Induces Maternal Tolerance to the Allogeneic Fetus in Abortion-Prone Matings.
L.-P. Jin, D.-J. Li, J.-P. Zhang, M.-Y. Wang, X.-Y. Zhu, Y. Zhu, Y. Meng, and M.-M. Yuan (2004)
J. Immunol. 173, 3612-3619
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MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4).
W. Stohl, D. Xu, K. S. Kim, C. S. David, and J. P. Allison (2004)
Int. Immunol. 16, 895-904
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In Situ Tumor Ablation Creates an Antigen Source for the Generation of Antitumor Immunity.
M. H. M. G. M. den Brok, R. P. M. Sutmuller, R. van der Voort, E. J. Bennink, C. G. Figdor, T. J. M. Ruers, and G. J. Adema (2004)
Cancer Res. 64, 4024-4029
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Identification of Protein-Protein Interfaces Implicated in CD80-CD28 Costimulatory Signaling.
P. Sorensen, M. Kussmann, A. Rosen, K. L. Bennett, D. d. G. Thrige, K. Uvebrant, B. Walse, P. Roepstorff, and P. Bjork (2004)
J. Immunol. 172, 6803-6809
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CTLA-4 Blockage Increases Resistance to Infection with the Intracellular Protozoan Trypanosoma cruzi.
G. A. Martins, C. E. Tadokoro, R. B. Silva, J. S. Silva, and L. V. Rizzo (2004)
J. Immunol. 172, 4893-4901
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CD86 and CD80 Differentially Modulate the Suppressive Function of Human Regulatory T Cells.
Y. Zheng, C. N. Manzotti, M. Liu, F. Burke, K. I. Mead, and D. M. Sansom (2004)
J. Immunol. 172, 2778-2784
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PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells.
C. Blank, I. Brown, A. C. Peterson, M. Spiotto, Y. Iwai, T. Honjo, and T. F. Gajewski (2004)
Cancer Res. 64, 1140-1145
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Importance of IL-10 for CTLA-4-Mediated Inhibition of Tumor-Eradicating Immunity.
V. M. Jovasevic, L. Gorelik, J. A. Bluestone, and M. B. Mokyr (2004)
J. Immunol. 172, 1449-1454
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Activity and Safety of CTLA-4 Blockade Combined with Vaccines in Cynomolgus Macaques.
T. Keler, E. Halk, L. Vitale, T. O'Neill, D. Blanset, S. Lee, M. Srinivasan, R. F. Graziano, T. Davis, N. Lonberg, et al. (2003)
J. Immunol. 171, 6251-6259
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Potentiation of Therapeutic Immune Responses against Malignancies with Monoclonal Antibodies.
O. Murillo, A. Arina, I. Tirapu, C. Alfaro, G. Mazzolini, B. Palencia, A. L.-D. De Cerio, J. Prieto, M. Bendandi, and I. Melero (2003)
Clin. Cancer Res. 9, 5454-5464
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Multivalent RNA Aptamers That Inhibit CTLA-4 and Enhance Tumor Immunity.
S. Santulli-Marotto, S. K. Nair, C. Rusconi, B. Sullenger, and E. Gilboa (2003)
Cancer Res. 63, 7483-7489
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B7x: A widely expressed B7 family member that inhibits T cell activation.
X. Zang, P'n. Loke, J. Kim, K. Murphy, R. Waitz, and J. P. Allison (2003)
PNAS 100, 10388-10392
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The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases.
S. A. Caldwell, M. H. Ryan, E. McDuffie, and S. I. Abrams (2003)
J. Immunol. 171, 2402-2412
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Inhibitory Signal Override Increases Susceptibility to Mercury-Induced Autoimmunity.
Y. Zheng and M. Monestier (2003)
J. Immunol. 171, 1596-1601
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Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
G. Q. Phan, J. C. Yang, R. M. Sherry, P. Hwu, S. L. Topalian, D. J. Schwartzentruber, N. P. Restifo, L. R. Haworth, C. A. Seipp, L. J. Freezer, et al. (2003)
PNAS 100, 8372-8377
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Generation of Antitumor Immunity by Cytotoxic T Lymphocyte Epitope Peptide Vaccination, CpG-oligodeoxynucleotide Adjuvant, and CTLA-4 Blockade.
E. Davila, R. Kennedy, and E. Celis (2003)
Cancer Res. 63, 3281-3288
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Vaccine Therapy of Established Tumors in the Absence of Autoimmunity.
J. W. Hodge, D. W. Grosenbach, W. M. Aarts, D. J. Poole, and J. Schlom (2003)
Clin. Cancer Res. 9, 1837-1849
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Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
F. S. Hodi, M. C. Mihm, R. J. Soiffer, F. G. Haluska, M. Butler, M. V. Seiden, T. Davis, R. Henry-Spires, S. MacRae, A. Willman, et al. (2003)
PNAS 100, 4712-4717
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CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model.
J. Espenschied, J. Lamont, J. Longmate, S. Pendas, Z. Wang, D. J. Diamond, and J. D. I. Ellenhorn (2003)
J. Immunol. 170, 3401-3407
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Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.
Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. Minato (2002)
PNAS 99, 12293-12297
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