This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Zaremba, S. Articles by Schlom, J. Search for Related Content PubMed PubMed Citation Articles by Zaremba, S. Articles by Schlom, J.

Identification of an Enhancer Agonist Cytotoxic T Lymphocyte Peptide from Human Carcinoembryonic Antigen

Laboratory of Tumor Immunology and Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892-1750

A vaccination strategy designed to enhance the immunogenicity of self-antigens that are overexpressed in tumor cells is to identify and slightly modify immunodominant epitopes that elicit T-cell responses. The resultant T cells, however, must maintain their ability to recognize the native configuration of the peptide-MHC interaction on the tumor cell target. We used a strategy to enhance the immunogenicity of a human CTL epitope directed against a human self-antigen, which involved the modification of individual amino acid residues predicted to interact with the T-cell receptor; this strategy, moreover, required no prior knowledge of these actual specific interactions. Single amino acid substitutions were introduced to the CAP1 peptide (YLSGANLNL), an immunogenic HLA-A2⁺-binding peptide derived from human carcinoembryonic antigen (CEA). In this study, four amino acid residues that were predicted to potentially interact with the T-cell receptor of CAP1-specific CTLs were systematically replaced. Analogues were tested for binding to HLA-A2 and for recognition by an established CTL line directed against CAP1. This line was obtained from peripheral blood mononuclear cells from an HLA-A2⁺ individual vaccinated with a vaccinia-CEA recombinant. An analogue peptide was identified that was capable of sensitizing CAP1-specific CTLs 10²–10³ times more efficiently than the native CAP1 peptide. This enhanced recognition was shown not to be due to better binding to HLA-A2. Therefore, the analogue CAP1-6D (YLSGADLNL, Asn at position 6 replaced by Asp) meets the criteria of a CTL enhancer agonist peptide. Both the CAP1-6D and the native CAP1 peptide were compared for the ability to generate specific CTL lines in vitro from unimmunized apparently healthy HLA-A2⁺ donors. Whereas CAP1 failed to generate CTLs from normal peripheral blood mononuclear cells, the agonist peptide was able to generate CD8⁺ CTL lines that recognized both the agonist and the native CAP1 sequence. Most importantly, these CTLs were capable of lysing human tumor cells endogenously expressing CEA. The use of enhancer agonist CTL peptides may thus represent a new efficient direction for immunotherapy protocols.

¹ S. Z. and E. B. contributed equally to this study and should be considered first authors.

² To whom requests for reprints should be addressed, at NIH, 9000 Rockville Pike, Building 10, Room 8B07, Bethesda, MD 20892-1750.

Received 6/ 5/97. Accepted 8/16/97.

This article has been cited by other articles:

				K. Rezvani, A. S. M. Yong, A. Tawab, B. Jafarpour, R. Eniafe, S. Mielke, B. N. Savani, K. Keyvanfar, Y. Li, R. Kurlander, et al. Ex vivo characterization of polyclonal memory CD8+ T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia Blood, March 5, 2009; 113(10): 2245 - 2255. [Abstract] [Full Text] [PDF]

				M. Barve, J. Bender, N. Senzer, C. Cunningham, F. A. Greco, D. McCune, R. Steis, H. Khong, D. Richards, J. Stephenson, et al. Induction of Immune Responses and Clinical Efficacy in a Phase II Trial of IDM-2101, a 10-Epitope Cytotoxic T-Lymphocyte Vaccine, in Metastatic Non-Small-Cell Lung Cancer J. Clin. Oncol., September 20, 2008; 26(27): 4418 - 4425. [Abstract] [Full Text] [PDF]

				H. L. Kaufman, H.-J. Lenz, J. Marshall, D. Singh, C. Garett, C. Cripps, M. Moore, M. von Mehren, R. Dalfen, W. J. Heim, et al. Combination Chemotherapy and ALVAC-CEA/B7.1 Vaccine in Patients with Metastatic Colorectal Cancer Clin. Cancer Res., August 1, 2008; 14(15): 4843 - 4849. [Abstract] [Full Text] [PDF]

				J. L. Gulley, P. M. Arlen, K.-Y. Tsang, J. Yokokawa, C. Palena, D. J. Poole, C. Remondo, V. Cereda, J. L. Jones, M. P. Pazdur, et al. Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma Clin. Cancer Res., May 15, 2008; 14(10): 3060 - 3069. [Abstract] [Full Text] [PDF]

				Y. Hou, B. Kavanagh, and L. Fong Distinct CD8+ T Cell Repertoires Primed with Agonist and Native Peptides Derived from a Tumor-Associated Antigen J. Immunol., February 1, 2008; 180(3): 1526 - 1534. [Abstract] [Full Text] [PDF]

				A. H. Dzutsev, I. M. Belyakov, D. V. Isakov, D. H. Margulies, and J. A. Berzofsky Avidity of CD8 T cells sharpens immunodominance Int. Immunol., April 1, 2007; 19(4): 497 - 507. [Abstract] [Full Text] [PDF]

				A. Saha, S. K. Chatterjee, K. A. Foon, E. Celis, and M. Bhattacharya-Chatterjee Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen Cancer Res., March 15, 2007; 67(6): 2881 - 2892. [Abstract] [Full Text] [PDF]

				Z. C. Hartman, A. Kiang, R. S. Everett, D. Serra, X. Y. Yang, T. M. Clay, and A. Amalfitano Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo J. Virol., February 15, 2007; 81(4): 1796 - 1812. [Abstract] [Full Text] [PDF]

				F. Carnevale-Schianca, A. Cignetti, A. Capaldi, K. Vitaggio, A. Vallario, A. Ricchiardi, E. Sperti, R. Ferraris, M. Gatti, G. Grignani, et al. Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD Blood, May 1, 2006; 107(9): 3795 - 3803. [Abstract] [Full Text] [PDF]

				M. R. Weihrauch, S. Ansen, E. Jurkiewicz, C. Geisen, Z. Xia, K. S. Anderson, E. Gracien, M. Schmidt, B. Wittig, V. Diehl, et al. Phase I/II Combined Chemoimmunotherapy with Carcinoembryonic Antigen-Derived HLA-A2-Restricted CAP-1 Peptide and Irinotecan, 5-Fluorouracil, and Leucovorin in Patients with Primary Metastatic Colorectal Cancer Clin. Cancer Res., August 15, 2005; 11(16): 5993 - 6001. [Abstract] [Full Text] [PDF]

				C. E. Clark and R. H. Vonderheide Getting to the Surface: A Link Between Tumor Antigen Discovery and Natural Presentation of Peptide-MHC Complexes Clin. Cancer Res., August 1, 2005; 11(15): 5333 - 5336. [Full Text] [PDF]

				S. Yang, K.-Y. Tsang, and J. Schlom Induction of Higher-Avidity Human CTLs by Vector-Mediated Enhanced Costimulation of Antigen-Presenting Cells Clin. Cancer Res., August 1, 2005; 11(15): 5603 - 5615. [Abstract] [Full Text] [PDF]

				M. A. Morse, T. M. Clay, A. C. Hobeika, T. Osada, S. Khan, S. Chui, D. Niedzwiecki, D. Panicali, J. Schlom, and H. K. Lyerly Phase I Study of Immunization with Dendritic Cells Modified with Fowlpox Encoding Carcinoembryonic Antigen and Costimulatory Molecules Clin. Cancer Res., April 15, 2005; 11(8): 3017 - 3024. [Abstract] [Full Text] [PDF]

				K. Y. Tsang, C. Palena, J. Yokokawa, P. M. Arlen, J. L. Gulley, G. P. Mazzara, L. Gritz, A. Gomez Yafal, S. Ogueta, P. Greenhalgh, et al. Analyses of Recombinant Vaccinia and Fowlpox Vaccine Vectors Expressing Transgenes for Two Human Tumor Antigens and Three Human Costimulatory Molecules Clin. Cancer Res., February 15, 2005; 11(4): 1597 - 1607. [Abstract] [Full Text] [PDF]

				J. L. Marshall, J. L. Gulley, P. M. Arlen, P. K. Beetham, K.-Y. Tsang, R. Slack, J. W. Hodge, S. Doren, D. W. Grosenbach, J. Hwang, et al. Phase I Study of Sequential Vaccinations With Fowlpox-CEA(6D)-TRICOM Alone and Sequentially With Vaccinia-CEA(6D)-TRICOM, With and Without Granulocyte-Macrophage Colony-Stimulating Factor, in Patients With Carcinoembryonic Antigen-Expressing Carcinomas J. Clin. Oncol., February 1, 2005; 23(4): 720 - 731. [Abstract] [Full Text] [PDF]

				H. L. Kaufman Integrating Bench With Bedside: The Role of Vaccine Therapy in the Treatment of Solid Tumors J. Clin. Oncol., February 1, 2005; 23(4): 659 - 661. [Full Text] [PDF]

				J. Bae, J. A. Martinson, and H. G. Klingemann Heteroclitic CD33 Peptide With Enhanced Anti-Acute Myeloid Leukemic Immunogenicity Clin. Cancer Res., October 15, 2004; 10(20): 7043 - 7052. [Abstract] [Full Text] [PDF]

				C. Palena, M. Zhu, J. Schlom, and K.-Y. Tsang Human B cells that hyperexpress a triad of costimulatory molecules via avipox-vector infection: an alternative source of efficient antigen-presenting cells Blood, July 1, 2004; 104(1): 192 - 199. [Abstract] [Full Text] [PDF]

				M. Ruiz, H. Kobayashi, J. J. Lasarte, J. Prieto, F. Borras-Cuesta, E. Celis, and P. Sarobe Identification and Characterization of a T-Helper Peptide from Carcinoembryonic Antigen Clin. Cancer Res., April 15, 2004; 10(8): 2860 - 2867. [Abstract] [Full Text] [PDF]

				S. Oh, M. Terabe, C. D. Pendleton, A. Bhattacharyya, T. K. Bera, M. Epel, Y. Reiter, J. Phillips, W. M. Linehan, C. Kasten-Sportes, et al. Human CTLs to Wild-Type and Enhanced Epitopes of a Novel Prostate and Breast Tumor-Associated Protein, TARP, Lyse Human Breast Cancer Cells Cancer Res., April 1, 2004; 64(7): 2610 - 2618. [Abstract] [Full Text] [PDF]

				K.-Y. Tsang, C. Palena, J. Gulley, P. Arlen, and J. Schlom A Human Cytotoxic T-Lymphocyte Epitope and Its Agonist Epitope from the Nonvariable Number of Tandem Repeat Sequence of MUC-1 Clin. Cancer Res., March 15, 2004; 10(6): 2139 - 2149. [Abstract] [Full Text] [PDF]

				G. Campi, M. Crosti, G. Consogno, V. Facchinetti, B. M. Conti-Fine, R. Longhi, G. Casorati, P. Dellabona, and M. P. Protti CD4+ T Cells from Healthy Subjects and Colon Cancer Patients Recognize a Carcinoembryonic Antigen-specific Immunodominant Epitope Cancer Res., December 1, 2003; 63(23): 8481 - 8486. [Abstract] [Full Text] [PDF]

				T. Okazaki, C. D. Pendleton, F. Lemonnier, and J. A. Berzofsky Epitope-Enhanced Conserved HIV-1 Peptide Protects HLA-A2-Transgenic Mice Against Virus Expressing HIV-1 Antigen J. Immunol., September 1, 2003; 171(5): 2548 - 2555. [Abstract] [Full Text] [PDF]

				C. Palena, J. Schlom, and K.-Y. Tsang Differential Gene Expression Profiles in a Human T-cell Line Stimulated with a Tumor-associated Self-peptide versus an Enhancer Agonist Peptide Clin. Cancer Res., May 1, 2003; 9(5): 1616 - 1627. [Abstract] [Full Text] [PDF]

				C. L Smith, N. Dulphy, M. Salio, and V. Cerundolo Immunotherapy of colorectal cancer Br. Med. Bull., December 1, 2002; 64(1): 181 - 200. [Abstract] [Full Text] [PDF]

				E. S. Kass, J. W. Greiner, J. A. Kantor, K. Y. Tsang, F. Guadagni, Z. Chen, B. Clark, R. D. Pascalis, J. Schlom, and C. Van Waes Carcinoembryonic Antigen as a Target for Specific Antitumor Immunotherapy of Head and Neck Cancer Cancer Res., September 1, 2002; 62(17): 5049 - 5057. [Abstract] [Full Text] [PDF]

				E. Huarte, P. Sarobe, J. Lu, N. Casares, J. J. Lasarte, J. Dotor, M. Ruiz, J. Prieto, E. Celis, and F. Borras-Cuesta Enhancing Immunogenicity of a CTL Epitope from Carcinoembryonic Antigen by Selective Amino Acid Replacements Clin. Cancer Res., July 1, 2002; 8(7): 2336 - 2344. [Abstract] [Full Text] [PDF]

				N. L. Berinstein Carcinoembryonic Antigen as a Target for Therapeutic Anticancer Vaccines: A Review J. Clin. Oncol., April 15, 2002; 20(8): 2197 - 2207. [Abstract] [Full Text] [PDF]

				C. Buteau, S. N. Markovic, and E. Celis Challenges in the Development of Effective Peptide Vaccines for Cancer Mayo Clin. Proc., April 1, 2002; 77(4): 339 - 349. [Abstract] [PDF]

				T. K. Hoffmann, D. J. Loftus, K. Nakano, M. J. Maeurer, K. Chikamatsu, E. Appella, T. L. Whiteside, and A. B. DeLeo The Ability of Variant Peptides to Reverse the Nonresponsiveness of T Lymphocytes to the Wild-Type Sequence p53264-272 Epitope J. Immunol., February 1, 2002; 168(3): 1338 - 1347. [Abstract] [Full Text] [PDF]

				H. Terasawa, K.-Y. Tsang, J. Gulley, P. Arlen, and J. Schlom Identification and Characterization of a Human Agonist Cytotoxic T-Lymphocyte Epitope of Human Prostate-specific Antigen Clin. Cancer Res., January 1, 2002; 8(1): 41 - 53. [Abstract] [Full Text] [PDF]

				K. Y. Tsang, M. Zhu, J. Even, J. Gulley, P. Arlen, and J. Schlom The Infection of Human Dendritic Cells with Recombinant Avipox Vectors Expressing a Costimulatory Molecule Transgene (CD80) to Enhance the Activation of Antigen-specific Cytolytic T Cells Cancer Res., October 1, 2001; 61(20): 7568 - 7576. [Abstract] [Full Text] [PDF]

				S. Tangri, G. Y. Ishioka, X. Huang, J. Sidney, S. Southwood, J. Fikes, and A. Sette Structural Features of Peptide Analogs of Human Histocompatibility Leukocyte Antigen Class I Epitopes That Are More Potent and Immunogenic than Wild-Type Peptide J. Exp. Med., September 17, 2001; 194(6): 833 - 846. [Abstract] [Full Text] [PDF]

				M. Zhu, H. Terasawa, J. Gulley, D. Panicali, P. Arlen, J. Schlom, and K. Y. Tsang Enhanced Activation of Human T Cells via Avipox Vector-mediated Hyperexpression of a Triad of Costimulatory Molecules in Human Dendritic Cells Cancer Res., May 1, 2001; 61(9): 3725 - 3734. [Abstract] [Full Text]

				M. von Mehren, P. Arlen, J. Gulley, A. Rogatko, H. S. Cooper, N. J. Meropol, R. K. Alpaugh, M. Davey, S. McLaughlin, M. T. Beard, et al. The Influence of Granulocyte Macrophage Colony-Stimulating Factor and Prior Chemotherapy on the Immunological Response to a Vaccine (ALVAC-CEA B7.1) in Patients with Metastatic Carcinoma Clin. Cancer Res., May 1, 2001; 7(5): 1181 - 1191. [Abstract] [Full Text]

				J. L. Marshall, R. J. Hoyer, M. A. Toomey, K. Faraguna, P. Chang, E. Richmond, J. E. Pedicano, E. Gehan, R. A. Peck, P. Arlen, et al. Phase I Study in Advanced Cancer Patients of a Diversified Prime-and-Boost Vaccination Protocol Using Recombinant Vaccinia Virus and Recombinant Nonreplicating Avipox Virus to Elicit Anti-Carcinoembryonic Antigen Immune Responses J. Clin. Oncol., December 1, 2000; 18(23): 3964 - 3973. [Abstract] [Full Text] [PDF]

				M. von Mehren, P. Arlen, K. Y. Tsang, A. Rogatko, N. Meropol, H. S. Cooper, M. Davey, S. McLaughlin, J. Schlom, and L. M. Weiner Pilot Study of a Dual Gene Recombinant Avipox Vaccine Containing Both Carcinoembryonic Antigen (CEA) and B7.1 Transgenes in Patients with Recurrent CEA-expressing Adenocarcinomas Clin. Cancer Res., June 1, 2000; 6(6): 2219 - 2228. [Abstract] [Full Text]

				N. G. Saito, H.-C. Chang, and Y. Paterson Recognition of an MHC Class I-Restricted Antigenic Peptide Can Be Modulated by para-Substitution of Its Buried Tyrosine Residues in a TCR-Specific Manner J. Immunol., May 15, 1999; 162(10): 5998 - 6008. [Abstract] [Full Text] [PDF]

				J. L. Marshall, M. J. Hawkins, K. Y. Tsang, E. Richmond, J. E. Pedicano, M. Zhu, and J. Schlom Phase I Study in Cancer Patients of a Replication-Defective Avipox Recombinant Vaccine That Expresses Human Carcinoembryonic Antigen J. Clin. Oncol., January 1, 1999; 17(1): 332 - 332. [Abstract] [Full Text] [PDF]

				L. Fong, Y. Hou, A. Rivas, C. Benike, A. Yuen, G. A. Fisher, M. M. Davis, and E. G. Engleman Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy PNAS, July 17, 2001; 98(15): 8809 - 8814. [Abstract] [Full Text] [PDF]