Original Article

Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine: Comparison of Prophylaxis and Therapy

Correspondence to: James P. Allison, HHMI/Cancer Research Lab, 401 LSA UC Berkeley, Berkeley, CA 94720. Tel:510-643-6012 Fax:510-643-5692 E-mail:jallison{at}uclink4.berkeley.edu.

We have previously shown that small B16 melanomas can be successfully treated using a combination of anti–cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibody with a granulocyte/macrophage colony-stimulating factor (GM-CSF) producing irradiated tumor cell vaccine. Regression of tumors results in long-lasting immunity and is frequently accompanied by autoimmune depigmentation. Here we examine the cellular and molecular mechanisms of this combined treatment. Histological examination of depigmented lesions revealed infiltration of polymorphonuclear cells and deposition of antibody. The combination therapy also induced tumor rejection and skin depigmentation in B cell–deficient and in CD4⁺ T cell–depleted mice. Both effects of the treatment absolutely required CD8⁺ T cells. Analysis of the response in successfully treated mice revealed elevated levels of CD8⁺ T cells specific for a nonameric peptide consisting of residues 180–188 of the melanocyte differentiation antigen tyrosinase-related protein (TRP)2. There was no evidence of reactivity to the melanocyte antigens gp100, tyrosinase, Mart1/MelanA, or TRP1. Fas–FasL interactions and perforin played a role in mounting the effector response, whereas the tumor necrosis factor pathway was not required. The cellular requirements for tumor rejection in this therapeutic setting were strikingly different from those in a prophylactic setting. In particular, if mice received a prophylactic vaccine consisting of anti–CTLA-4 and B16–GM-CSF before tumor challenge, full protection was obtained even in the absence of CD8⁺ T cells. Our data demonstrate that therapeutic autoreactive CD8⁺ T cell responses can effectively be generated in tumor-bearing mice and stresses the value of studying tumor immunity in a therapeutic rather than a prophylactic setting.

Key Words: immunotherapy, prophylaxis, T lymphocyte, TRP-2, depigmentation

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Lin, Y.-C., Chang, L.-Y., Huang, C.-T., Peng, H.-M., Dutta, A., Chen, T.-C., Yeh, C.-T., Lin, C.-Y. (2009). Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity. J. Immunol. 182: 6095-6104 [Abstract] [Full Text]  
• Klein, O., Ebert, L. M., Nicholaou, T., Browning, J., Russell, S. E., Zuber, M., Jackson, H. M., Dimopoulos, N., Tan, B. S., Hoos, A., Luescher, I. F., Davis, I. D., Chen, W., Cebon, J. (2009). Melan-A-specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4. Clin. Cancer Res. 15: 2507-2513 [Abstract] [Full Text]  
• Li, B., VanRoey, M., Wang, C., Chen, T.-h. T., Korman, A., Jooss, K. (2009). Anti-Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors. Clin. Cancer Res. 15: 1623-1634 [Abstract] [Full Text]  
• Fong, L., Kwek, S. S., O'Brien, S., Kavanagh, B., McNeel, D. G., Weinberg, V., Lin, A. M., Rosenberg, J., Ryan, C. J., Rini, B. I., Small, E. J. (2009). Potentiating Endogenous Antitumor Immunity to Prostate Cancer through Combination Immunotherapy with CTLA4 Blockade and GM-CSF. Cancer Res. 69: 609-615 [Abstract] [Full Text]  
• Ribas, A., Comin-Anduix, B., Economou, J. S., Donahue, T. R., de la Rocha, P., Morris, L. F., Jalil, J., Dissette, V. B., Shintaku, I. P., Glaspy, J. A., Gomez-Navarro, J., Cochran, A. J. (2009). Intratumoral Immune Cell Infiltrates, FoxP3, and Indoleamine 2,3-Dioxygenase in Patients with Melanoma Undergoing CTLA4 Blockade. Clin. Cancer Res. 15: 390-399 [Abstract] [Full Text]  
• Yuan, J., Gnjatic, S., Li, H., Powel, S., Gallardo, H. F., Ritter, E., Ku, G. Y., Jungbluth, A. A., Segal, N. H., Rasalan, T. S., Manukian, G., Xu, Y., Roman, R.-A., Terzulli, S. L., Heywood, M., Pogoriler, E., Ritter, G., Old, L. J., Allison, J. P., Wolchok, J. D. (2008). CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc. Natl. Acad. Sci. USA 105: 20410-20415 [Abstract] [Full Text]  
• Weber, J. S., O'Day, S., Urba, W., Powderly, J., Nichol, G., Yellin, M., Snively, J., Hersh, E. (2008). Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma. JCO 26: 5950-5956 [Abstract] [Full Text]  
• Phan, G. Q., Weber, J. S., Sondak, V. K. (2008). CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues. Ann. Surg. Oncol. 15: 3014-3021 [Abstract] [Full Text]  
• Wolchok, J. D., Saenger, Y. (2008). The Mechanism of Anti-CTLA-4 Activity and the Negative Regulation of T-Cell Activation. The Oncologist 13: 2-9 [Abstract] [Full Text]  
• King, J., Waxman, J., Stauss, H. (2008). Advances in tumour immunotherapy. QJM 101: 675-683 [Abstract] [Full Text]  
• Kavanagh, B., O'Brien, S., Lee, D., Hou, Y., Weinberg, V., Rini, B., Allison, J. P., Small, E. J., Fong, L. (2008). CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 112: 1175-1183 [Abstract] [Full Text]  
• Fasso, M., Waitz, R., Hou, Y., Rim, T., Greenberg, N. M., Shastri, N., Fong, L., Allison, J. P. (2008). SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade. Proc. Natl. Acad. Sci. USA 105: 3509-3514 [Abstract] [Full Text]  
• Moeller, M., Kershaw, M. H., Cameron, R., Westwood, J. A., Trapani, J. A., Smyth, M. J., Darcy, P. K. (2007). Sustained Antigen-Specific Antitumor Recall Response Mediated by Gene-Modified CD4+ T Helper-1 and CD8+ T Cells. Cancer Res. 67: 11428-11437 [Abstract] [Full Text]  
• Kochenderfer, J. N., Gress, R. E. (2007). A Comparison and Critical Analysis of Preclinical Anticancer Vaccination Strategies. Exp. Biol. Med. 232: 1130-1141 [Abstract] [Full Text]  
• Hodi, F. S. (2007). Cytotoxic T-Lymphocyte Associated Antigen-4. Clin. Cancer Res. 13: 5238-5242 [Abstract] [Full Text]  
• Ribas, A., Hanson, D. C., Noe, D. A., Millham, R., Guyot, D. J., Bernstein, S. H., Canniff, P. C., Sharma, A., Gomez-Navarro, J. (2007). Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer. The Oncologist 12: 873-883 [Abstract] [Full Text]  
• Kochenderfer, J. N., Simpson, J. L., Chien, C. D., Gress, R. E. (2007). Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT. Blood 110: 450-460 [Abstract] [Full Text]  
• O'Mahony, D., Morris, J. C., Quinn, C., Gao, W., Wilson, W. H., Gause, B., Pittaluga, S., Neelapu, S., Brown, M., Fleisher, T. A., Gulley, J. L., Schlom, J., Nussenblatt, R., Albert, P., Davis, T. A., Lowy, I., Petrus, M., Waldmann, T. A., Janik, J. E. (2007). A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy. Clin. Cancer Res. 13: 958-964 [Abstract] [Full Text]  
• Kochenderfer, J. N., Chien, C. D., Simpson, J. L., Gress, R. E. (2006). Synergism between CpG-Containing Oligodeoxynucleotides and IL-2 Causes Dramatic Enhancement of Vaccine-Elicited CD8+ T Cell Responses. J. Immunol. 177: 8860-8873 [Abstract] [Full Text]  
• Gattinoni, L., Ranganathan, A., Surman, D. R., Palmer, D. C., Antony, P. A., Theoret, M. R., Heimann, D. M., Rosenberg, S. A., Restifo, N. P. (2006). CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent. Blood 108: 3818-3823 [Abstract] [Full Text]  
• Doyle, H. A., Zhou, J., Wolff, M. J., Harvey, B. P., Roman, R. M., Gee, R. J., Koski, R. A., Mamula, M. J. (2006). Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity. J. Biol. Chem. 281: 32676-32683 [Abstract] [Full Text]  
• Lee, C.-h., Kakinuma, T., Wang, J., Zhang, H., Palmer, D. C., Restifo, N. P., Hwang, S. T. (2006). Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases.. Molecular Cancer Therapeutics 5: 2592-2599 [Abstract] [Full Text]  
• Kocak, E., Lute, K., Chang, X., May, K. F. Jr., Exten, K. R., Zhang, H., Abdessalam, S. F., Lehman, A. M., Jarjoura, D., Zheng, P., Liu, Y. (2006). Combination Therapy with Anti-CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity.. Cancer Res. 66: 7276-7284 [Abstract] [Full Text]  
• McWilliams, J. A., McGurran, S. M., Dow, S. W., Slansky, J. E., Kedl, R. M. (2006). A Modified Tyrosinase-Related Protein 2 Epitope Generates High-Affinity Tumor-Specific T Cells but Does Not Mediate Therapeutic Efficacy in an Intradermal Tumor Model. J. Immunol. 177: 155-161 [Abstract] [Full Text]  
• Kaufman, H. L., Wolchok, J. D. (2006). Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer Immunotherapy. JCO 24: 2230-2232 [Full Text]  
• Kryczek, I., Zou, L., Rodriguez, P., Zhu, G., Wei, S., Mottram, P., Brumlik, M., Cheng, P., Curiel, T., Myers, L., Lackner, A., Alvarez, X., Ochoa, A., Chen, L., Zou, W. (2006). B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. JEM 203: 871-881 [Abstract] [Full Text]  
• Kapadia, D., Fong, L. (2005). CTLA-4 Blockade: Autoimmunity As Treatment. JCO 23: 8926-8928 [Full Text]  
• Lute, K. D., May, K. F. Jr, Lu, P., Zhang, H., Kocak, E., Mosinger, B., Wolford, C., Phillips, G., Caligiuri, M. A., Zheng, P., Liu, Y. (2005). Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood 106: 3127-3133 [Abstract] [Full Text]  
• Schneider, H., Valk, E., da Rocha Dias, S., Wei, B., Rudd, C. E. (2005). CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc. Natl. Acad. Sci. USA 102: 12861-12866 [Abstract] [Full Text]  
• Ji, Q., Gondek, D., Hurwitz, A. A. (2005). Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response. J. Immunol. 175: 1456-1463 [Abstract] [Full Text]  
• Esplugues, E., Vega-Ramos, J., Cartoixa, D., Vazquez, B. N., Salaet, I., Engel, P., Lauzurica, P. (2005). Induction of tumor NK-cell immunity by anti-CD69 antibody therapy. Blood 105: 4399-4406 [Abstract] [Full Text]  
• Hodge, J. W., Chakraborty, M., Kudo-Saito, C., Garnett, C. T., Schlom, J. (2005). Multiple Costimulatory Modalities Enhance CTL Avidity. J. Immunol. 174: 5994-6004 [Abstract] [Full Text]  
• Chiang, E. Y., Stroynowski, I. (2005). Protective Immunity against Disparate Tumors Is Mediated by a Nonpolymorphic MHC Class I Molecule. J. Immunol. 174: 5367-5374 [Abstract] [Full Text]  
• Yu, P., Lee, Y., Liu, W., Krausz, T., Chong, A., Schreiber, H., Fu, Y.-X. (2005). Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. JEM 201: 779-791 [Abstract] [Full Text]  
• May, K. F. Jr, Roychowdhury, S., Bhatt, D., Kocak, E., Bai, X.-F., Liu, J.-Q., Ferketich, A. K., Martin, E. W. Jr, Caligiuri, M. A., Zheng, P., Liu, Y. (2005). Anti-human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies. Blood 105: 1114-1120 [Abstract] [Full Text]  
• Demaria, S., Kawashima, N., Yang, A. M., Devitt, M. L., Babb, J. S., Allison, J. P., Formenti, S. C. (2005). Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer. Clin. Cancer Res. 11: 728-734 [Abstract] [Full Text]  
• Prasad, S. J., Farrand, K. J., Matthews, S. A., Chang, J. H., McHugh, R. S., Ronchese, F. (2005). Dendritic Cells Loaded with Stressed Tumor Cells Elicit Long-Lasting Protective Tumor Immunity in Mice Depleted of CD4+CD25+ Regulatory T Cells. J. Immunol. 174: 90-98 [Abstract] [Full Text]  
• De Palma, R., Marigo, I., Del Galdo, F., De Santo, C., Serafini, P., Cingarlini, S., Tuting, T., Lenz, J., Basso, G., Milan, G., Zanovello, P., Bronte, V. (2004). Therapeutic Effectiveness of Recombinant Cancer Vaccines Is Associated with a Prevalent T-Cell Receptor {alpha} Usage by Melanoma-specific CD8+ T Lymphocytes. Cancer Res. 64: 8068-8076 [Abstract] [Full Text]  
• Blattman, J. N., Greenberg, P. D. (2004). Cancer Immunotherapy: A Treatment for the Masses. Science 305: 200-205 [Abstract] [Full Text]  
• Ma, H.-L., Whitters, M. J., Jacobson, B. A., Donaldson, D. D., Collins, M., Dunussi-Joannopoulos, K. (2004). Tumor cells secreting IL-13 but not IL-13R{alpha}2 fusion protein have reduced tumorigenicity in vivo. Int Immunol 16: 1009-1017 [Abstract] [Full Text]  
• Madrenas, J., Chau, L. A., Teft, W. A., Wu, P. W., Jussif, J., Kasaian, M., Carreno, B. M., Ling, V. (2004). Conversion of CTLA-4 from Inhibitor to Activator of T Cells with a Bispecific Tandem Single-Chain Fv Ligand. J. Immunol. 172: 5948-5956 [Abstract] [Full Text]  
• Akazawa, T., Masuda, H., Saeki, Y., Matsumoto, M., Takeda, K., Tsujimura, K., Kuzushima, K., Takahashi, T., Azuma, I., Akira, S., Toyoshima, K., Seya, T. (2004). Adjuvant-Mediated Tumor Regression and Tumor-Specific Cytotoxic Response Are Impaired in MyD88-Deficient Mice. Cancer Res. 64: 757-764 [Abstract] [Full Text]  
• O'Mara, L. A., Allen, P. M. (2004). Pulmonary Tumors Inefficiently Prime Tumor-Specific T Cells. J. Immunol. 172: 310-317 [Abstract] [Full Text]  
• Prins, R. M., Odesa, S. K., Liau, L. M. (2003). Immunotherapeutic Targeting of Shared Melanoma-Associated Antigens in a Murine Glioma Model. Cancer Res. 63: 8487-8491 [Abstract] [Full Text]  
• Keler, T., Halk, E., Vitale, L., O'Neill, T., Blanset, D., Lee, S., Srinivasan, M., Graziano, R. F., Davis, T., Lonberg, N., Korman, A. (2003). Activity and Safety of CTLA-4 Blockade Combined with Vaccines in Cynomolgus Macaques. J. Immunol. 171: 6251-6259 [Abstract] [Full Text]  
• Santulli-Marotto, S., Nair, S. K., Rusconi, C., Sullenger, B., Gilboa, E. (2003). Multivalent RNA Aptamers That Inhibit CTLA-4 and Enhance Tumor Immunity. Cancer Res. 63: 7483-7489 [Abstract] [Full Text]  
• Ma, H.-L., Whitters, M. J., Konz, R. F., Senices, M., Young, D. A., Grusby, M. J., Collins, M., Dunussi-Joannopoulos, K. (2003). IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-{gamma}. J. Immunol. 171: 608-615 [Abstract] [Full Text]  
• Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., Morton, K. E., Mavroukakis, S. A., Duray, P. H., Steinberg, S. M., Allison, J. P., Davis, T. A., Rosenberg, S. A. (2003). Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA 100: 8372-8377 [Abstract] [Full Text]  
• Halin, C., Gafner, V., Villani, M. E., Borsi, L., Berndt, A., Kosmehl, H., Zardi, L., Neri, D. (2003). Synergistic Therapeutic Effects of a Tumor Targeting Antibody Fragment, Fused to Interleukin 12 and to Tumor Necrosis Factor {alpha}. Cancer Res. 63: 3202-3210 [Abstract] [Full Text]  
• Davila, E., Kennedy, R., Celis, E. (2003). Generation of Antitumor Immunity by Cytotoxic T Lymphocyte Epitope Peptide Vaccination, CpG-oligodeoxynucleotide Adjuvant, and CTLA-4 Blockade. Cancer Res. 63: 3281-3288 [Abstract] [Full Text]  
• Hodge, J. W., Grosenbach, D. W., Aarts, W. M., Poole, D. J., Schlom, J. (2003). Vaccine Therapy of Established Tumors in the Absence of Autoimmunity. Clin. Cancer Res. 9: 1837-1849 [Abstract] [Full Text]  
• Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M. T., Shankar, S., Chen, T. C., Korman, A., Allison, J. P., Dranoff, G. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl. Acad. Sci. USA 100: 4712-4717 [Abstract] [Full Text]  
• Espenschied, J., Lamont, J., Longmate, J., Pendas, S., Wang, Z., Diamond, D. J., Ellenhorn, J. D. I. (2003). CTLA-4 Blockade Enhances the Therapeutic Effect of an Attenuated Poxvirus Vaccine Targeting p53 in an Established Murine Tumor Model. J. Immunol. 170: 3401-3407 [Abstract] [Full Text]  
• Dechant, M., Vidarsson, G., Stockmeyer, B., Repp, R., Glennie, M. J., Gramatzki, M., van de Winkel, J. G. J., Valerius, T. (2002). Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing. Blood 100: 4574-4580 [Abstract] [Full Text]  
• Greiner, J. W., Zeytin, H., Anver, M. R., Schlom, J. (2002). Vaccine-based Therapy Directed against Carcinoembryonic Antigen Demonstrates Antitumor Activity on Spontaneous Intestinal Tumors in the Absence of Autoimmunity. Cancer Res. 62: 6944-6951 [Abstract] [Full Text]  
• Tsung, K., Dolan, J. P., Tsung, Y. L., Norton, J. A. (2002). Macrophages as Effector Cells in Interleukin 12-induced T Cell-dependent Tumor Rejection. Cancer Res. 62: 5069-5075 [Abstract] [Full Text]  
• Kalergis, A. M., Ravetch, J. V. (2002). Inducing Tumor Immunity through the Selective Engagement of Activating Fc{gamma} Receptors on Dendritic Cells. JEM 195: 1653-1659 [Abstract] [Full Text]  
• Seki, N., Brooks, A. D., Carter, C. R. D., Back, T. C., Parsoneault, E. M., Smyth, M. J., Wiltrout, R. H., Sayers, T. J. (2002). Tumor-Specific CTL Kill Murine Renal Cancer Cells Using Both Perforin and Fas Ligand-Mediated Lysis In Vitro, But Cause Tumor Regression In Vivo in the Absence of Perforin. J. Immunol. 168: 3484-3492 [Abstract] [Full Text]  
• Hurwitz, A. A., Sullivan, T. J., Sobel, R. A., Allison, J. P. (2002). Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice. Proc. Natl. Acad. Sci. USA 10.1073/pnas.042684699v1 [Abstract] [Full Text]  
• Steitz, J., Bruck, J., Lenz, J., Knop, J., Tuting, T. (2001). Depletion of CD25+ CD4+ T Cells and Treatment with Tyrosinase-related Protein 2-transduced Dendritic Cells Enhance the Interferon {alpha}-induced, CD8+ T-Cell-dependent Immune Defense of B16 Melanoma. Cancer Res. 61: 8643-8646 [Abstract] [Full Text]  
• Hurwitz, A. A., Sullivan, T. J., Sobel, R. A., Allison, J. P. (2002). Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice. Proc. Natl. Acad. Sci. USA 99: 3013-3017 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS