Cancer Antigen Discovery Program
Cancer Antigen Characterization
A critical part of the LICR approach to developing therapeutic cancer vaccines is a thorough characterization of defined cancer antigens to select the most appropriate candidates for clinical evaluation.
Introduction
Effective cancer vaccines must be able to induce broad, robust, long-lasting immune responses directed toward cancer antigens expressed in human tumors. Thus, once a cancer antigen has been identified, it is characterized to satisfy vaccine requirements based upon tumor-specific expression criteria, and immunogenicity.
Standard techniques, protocols, and reagents have been adopted and are consistently applied to ensure that these analyses are directly comparable between different LICR laboratories participating in this program.
Cancer Associated Expression
Cancer antigen expression is evaluated through extensive molecular biological and immunohistochemical (IHC) analyses of various human cancers and their corresponding normal tissues. Restricted tissue expression is important to ensure that a vaccine does not induce the immune system to attack healthy normal tissues that also express the cancer antigen. LICR has generated monoclonal antibodies that are specific for each cancer antigen undergoing preclinical and clinical evaluation for use in IHC. Each monoclonal antibody is rigorously validated for antigen specificity under conditions appropriate for analysis of both fresh and frozen (archival) tumor tissues. The antibodies are then used to search for antigen prevalence in normal human tissues. Additional monoclonal antibodies that are specific for antigenic HLA-peptide complexes are also being generated, which will provide more typing reagents for evaluating antigen expression on cancer cells.
In addition to characterizing the tissues in which the antigen is expressed, the prevalence and frequency of antigen expression is also be analyzed. The prevalence of a particular antigen may vary, meaning that not all tumors of a particular tumor-type may express the antigen at all. Many antigens have heterogeneous expression, with the result that the proportion of cells that express the antigen within each tumor may vary from patient to patient. A vaccine that targets an antigen expressed by a high proportion of tumor cells and that is highly prevalent (expressed in most patients) will be more efficacious and applicable, respectively, than a vaccine that targets an antigen with a low tumor expression frequency and in a small number of patients.
Immunogenicity
Further selection of clinically relevant antigens is based upon the analysis of the immune response against them in cancer patients. Detection of pre-existing or spontaneous immunity provides a basis for determining an antigen’s inherent immunogenicity. Methodologies have been developed for assessing both antibody and T cell antigen-specific immune responses (Immune Monitoring). For example, analyses of spontaneous immunity in patients with tumors expressing the NY-ESO-1 cancer antigen indicate the co-existence of NY-ESO-1-specific antibody, CD8+ T cell and CD4+ T cell responses. The observed ‘integrated’ (antibody plus T cell) immune response to NY-ESO-1 underscores this antigen’s immunogenicity and significance in the development of defined cancer vaccines.
Characterization of Spontaneous Immunity
Characterization of the spontaneous immune response to defined cancer antigens has led to the identification of specific antigenic peptide ‘epitopes’; short protein sequences that are recognized by antigen-specific CD8+ T and CD4+ T cells. Knowledge gained from identifying peptide epitope sequences can be applied directly to the characterization of antigen-specific immune responses following immunization with cancer vaccines, and to the further development of peptide-based cancer vaccines. Comparison of vaccine-induced immunity with naturally-induced or spontaneous immunity to the corresponding antigen contributes to the evaluation of the efficacy of a cancer vaccine.
Key Publications
- J. Tammela, A.A. Jungbluth, F. Qian, D. Santiago, M.J. Scanlan, B. Keitz, D. Driscoll, K. Rodabaugh, S. Lele, L.J. Old, and K. Odunsi. SCP-1 cancer/testis antigen is a prognostic indicator and a candidate target for immunotherapy in epithelial ovarian cancer. Cancer Immunity 4:10, 2004.
- S. Gnjatic, D. Atanackovic, E. Jager, M. Matsuo, A. Selvakumar, N.K. Altorki, R.G. Maki, B. Dupont, G. Ritter, Y.T. Chen, A. Knuth, and L.J. Old. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proceedings of the National Academy of Sciences USA 100(15):8862-8867, 2003.
- K. Odunsi, A.A. Jungbluth, E. Stockert, F. Qian, S. Gnjatic, J. Tammela, M. Intengan, A. Beck, B. Keitz, D. Santiago, B. Williamson, M.J. Scanlan, G. Ritter, Y.T. Chen, D. Driscoll, A. Sood, S. Lele, and L.J. Old. NY-ESO-1 and LAGE-1 Cancer-Testis Antigens Are Potential Targets for Immunotherapy in Epithelial Ovarian Cancer. Cancer Research (2003) 63(18):6076-6083, 2003.
- P. Romero, D. Valmori, M.J. Pittet, A. Zippelius, D. Rimoldi, F. Levy, V. Dutoit, M. Ayyoub, V. Rubio-Godoy, O. Michielin, P. Guillaume, P. Batard, I.F. Luescher, F. Lejeune, D. Lienard, N. Rufer, P.Y. Dietrich, D.E. Speiser, and J.C. Cerottini. Antigenicity and immunogenicity of Melan-A/MART-1 derived peptides as targets for tumor reactive CTL in human melanoma. Immunology Reviews 188:81-96, 2002.
- J.L. Chen, P.R. Dunbar, U. Gileadi, E. Jager, S. Gnjatic, Y. Nagata, E. Stockert, D.L. Panicali, Y.T. Chen, A. Knuth, L.J. Old, and V. Cerundolo. Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL. Journal of Immunology 165(2):948-955, 2000.
- D. Valmori, M.J. Pittet, C. Vonarbourg, D. Rimoldi, D. Lienard, D. Speiser, R. Dunbar, V. Cerundolo, J.C. Cerottini, and P. Romero. Analysis of the cytolytic T lymphocyte response of melanoma patients to the naturally HLA-A*0201-associated tyrosinase peptide 368-376. Cancer Research 59(16):4050-4055, 1999.