This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, J. Articles by Epstein, A. L. Search for Related Content PubMed PubMed Citation Articles by Li, J. Articles by Epstein, A. L.

Complete Regression of Experimental Solid Tumors by Combination LEC/chTNT-3 Immunotherapy and CD25⁺ T-Cell Depletion

Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California

LEC/chTNT-3, a chemokine fusion protein generated previously in our laboratory, produces a 40–60% reduction in well-established solid tumors of the BALB/c mouse. In this study, CD25⁺ T-cell depletion was used in combination with LEC/chTNT-3 treatment to enhance the therapeutic value of this approach. In two tumor models (Colon 26 and RENCA), this combination immunotherapy produced complete regression of established s.c. tumors after 5 consecutive days of i.v. treatment. To show that targeted LEC is critical to these results, similar combination studies were performed with chTNT-3/cytokine fusion proteins consisting of human interleukin 2, murine IFN-, and murine granulocyte macrophage colony-stimulating factor using identical treatment regimens. These studies showed no significant improvement indicating that combination therapy with anti-CD25⁺ antisera requires LEC localization to tumor to produce complete regression. To study the mechanism of this remarkable response, immunotherapeutic studies were repeated in knockout mice and showed that successful treatment with CD25⁺ depletion was dependent on the presence of IFN- but not perforin. Other studies using real-time PCR, ex vivo proliferation, and intracellular cytokine staining with lymphocytes from tumor draining lymph nodes, suggested that this combination treatment was associated with increased T-helper 1 cytokine expression, enhanced T-cell activation, and increased IFN- production by T cells. Rechallenge experiments showed that combination LEC/chTNT-3 treatment and CD25⁺ depletion produced long-acting memory cells capable of preventing re-engraftment of the same but not different tumor cell lines. These studies suggest that LEC/monoclonal antibody fusion proteins, when used in combination with CD25⁺ T-cell depletion, is a viable method of immunotherapy for the treatment of solid tumors.

This article has been cited by other articles:

				P. Hu, R. S. Arias, R. E. Sadun, Y.-C. Nien, N. Zhang, H. Sabzevari, M.E. C. Lutsiak, L. A. Khawli, and A. L. Epstein Construction and Preclinical Characterization of Fc-mGITRL for the Immunotherapy of Cancer Clin. Cancer Res., January 15, 2008; 14(2): 579 - 588. [Abstract] [Full Text] [PDF]

				R. E. Sadun, S. M. Sachsman, X. Chen, K. W. Christenson, W. Z. Morris, P. Hu, and A. L. Epstein Immune Signatures of Murine and Human Cancers Reveal Unique Mechanisms of Tumor Escape and New Targets for Cancer Immunotherapy Clin. Cancer Res., July 1, 2007; 13(13): 4016 - 4025. [Abstract] [Full Text] [PDF]

				N. Zhang, R. E. Sadun, R. S. Arias, M. L. Flanagan, S. M. Sachsman, Y.-C. Nien, L. A. Khawli, P. Hu, and A. L. Epstein Targeted and Untargeted CD137L Fusion Proteins for the Immunotherapy of Experimental Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2758 - 2767. [Abstract] [Full Text] [PDF]

				P. Cappello, T. Fraone, L. Barberis, C. Costa, E. Hirsch, A. R. Elia, C. Caorsi, T. Musso, F. Novelli, and M. Giovarelli CC-Chemokine Ligand 16 Induces a Novel Maturation Program in Human Immature Monocyte-Derived Dendritic Cells J. Immunol., November 1, 2006; 177(9): 6143 - 6151. [Abstract] [Full Text] [PDF]

				A. Comes, O. Rosso, A. M. Orengo, E. Di Carlo, C. Sorrentino, R. Meazza, T. Piazza, B. Valzasina, P. Nanni, M. P. Colombo, et al. CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine J. Immunol., February 1, 2006; 176(3): 1750 - 1758. [Abstract] [Full Text] [PDF]

				A. Liu, P. Hu, L. A. Khawli, and A. L. Epstein Combination B7-Fc Fusion Protein Treatment and Treg Cell Depletion Therapy Clin. Cancer Res., December 1, 2005; 11(23): 8492 - 8502. [Abstract] [Full Text] [PDF]

				C. Kudo-Saito, J. Schlom, K. Camphausen, C. N. Coleman, and J. W. Hodge The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors Clin. Cancer Res., June 15, 2005; 11(12): 4533 - 4544. [Abstract] [Full Text] [PDF]

				P. Yu, Y. Lee, W. Liu, T. Krausz, A. Chong, H. Schreiber, and Y.-X. Fu Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors J. Exp. Med., March 7, 2005; 201(5): 779 - 791. [Abstract] [Full Text] [PDF]

				Q. Zhang, X. Yang, M. Pins, B. Javonovic, T. Kuzel, S.-J. Kim, L. V. Parijs, N. M. Greenberg, V. Liu, Y. Guo, et al. Adoptive Transfer of Tumor-Reactive Transforming Growth Factor-{beta}-Insensitive CD8+ T Cells: Eradication of Autologous Mouse Prostate Cancer Cancer Res., March 1, 2005; 65(5): 1761 - 1769. [Abstract] [Full Text] [PDF]