Generation of CA125-specific cytotoxic T lymphocytes in human leukocyte antigen-A2.1-positive healthy donors and patients with advanced ovarian cancer

Published:November 03, 2008DOI:


      To identify potential immunogenic peptides derived from CA125.

      Study Design

      A bioinformatics approach was used to identify peptides derived from CA125 that bind to human leukocyte antigen A2.1 and elicit peptide-specific human cytotoxic T-lymphocyte responses in healthy individuals and patients with ovarian carcinoma.


      CD8+ cytotoxic T-lymphocyte populations generated against 4 CA125-derived peptides were able to induce lysis of autologous peptide-loaded target cells. CA125 YTLDrDSLYV peptide-specific cytotoxic T lymphocytes were found to effectively kill ovarian tumors expressing CA125. Cytotoxicity was inhibited by antihuman leukocyte antigen A2.1 (BB7-2) and antihuman leukocyte antigen class I (W6/32) antibodies, whereas natural killer-sensitive targets were not lysed. YTLDrDSLYV peptide-specific cytotoxic T lymphocyte precursor frequency was low in peripheral blood leukocytes of normal donors and patients with ovarian cancer as determined by interferon-gamma production in ELISPOT assays. Intracellular cytokine expression measured by flow cytometry showed a type 1 cytokine profile in YTLDrDSLYV peptide-specific cytotoxic T lymphocytes.


      The CA125 YTLDrDSLYV peptide is an immunogenic epitope and may represent an attractive target for immunotherapy of ovarian cancer.

      Key words

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        • Jemal A.
        • Siegel R.
        • Ward E.
        • Murray T.
        • Xu J.
        • Thun M.J.
        Cancer statistics, 2007.
        CA Cancer J Clin. 2007; 57: 43-66
        • DiSaia P.J.
        • Creasman W.T.
        Clinical gynecologic oncology: invasive cervical cancer.
        in: 5th ed. Mosby-Year Book, St Louis1997: 51-106
        • Bast Jr, R.C.
        • Feeney M.
        • Lazarus H.
        • Nadler L.M.
        • Colvin R.B.
        • Knapp R.C.
        Reactivity of a monoclonal antibody with human ovarian carcinoma.
        J Clin Invest. 1981; 68: 1331-1337
        • Bast Jr, R.C.
        • Badgwell D.
        • Lu Z.
        • et al.
        New tumor markers: CA125 and beyond.
        Int J Gynecol Cancer. 2005; 15: 274-281
        • Rustin G.J.
        • Nelstrop A.E.
        • McClean P.
        • et al.
        Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125.
        J Clin Oncol. 1996; 14: 1545-1551
        • Wagner U.
        • Kohler S.
        • Reinartz S.
        • et al.
        Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment.
        Clin Cancer Res. 2001; 7: 1154-1162
        • Reinartz S.
        • Kohler S.
        • Schlebusch H.
        • et al.
        Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).
        Clin Cancer Res. 2004; 10: 1580-1587
        • Berek J.S.
        • Taylor P.T.
        • Gordon A.
        • et al.
        Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.
        J Clin Oncol. 2004; 22: 3507-3516
        • Gordon A.N.
        • Schultes B.C.
        • Gallion H.
        • et al.
        CA125- and tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent ovarian cancer patients.
        Gynecol Oncol. 2004; 94: 340-351
        • Ehlen T.G.
        • Hoskins P.J.
        • Miller D.
        • et al.
        A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.
        Int J Gynecol Cancer. 2005; 15: 1023-1034
        • O'Brien T.J.
        • Beard J.B.
        • Underwood L.J.
        • Dennis R.A.
        • Santin A.D.
        • York L.
        The CA 125 gene: an extracellular superstructure dominated by repeat sequences.
        Tumour Biol. 2001; 22: 348-366
        • O'Brien T.J.
        • Beard J.B.
        • Underwood L.J.
        • Shigemasa K.
        The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure.
        Tumour Biol. 2002; 23: 154-169
        • Yin B.W.
        • Lloyd K.O.
        Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16.
        J Biol Chem. 2001; 276: 27371-27375
        • Zeh 3rd, H.J.
        • Leder G.H.
        • Lotze M.T.
        • et al.
        Flow-cytometric determination of peptide-class I complex formation: identification of p53 peptides that bind to HLA-A2.
        Human Immunol. 1994; 39: 79-86
        • Santin A.D.
        • Bellone S.
        • Ravaggi A.
        • Pecorelli S.
        • Cannon M.J.
        • Parham G.P.
        Induction of ovarian tumor-specific CD8+ cytotoxic T lymphocytes by acid-eluted peptide-pulsed autologous dendritic cells.
        Obstet Gynecol. 2000; 96: 422-430
        • Santin A.D.
        • Hermonat P.L.
        • Ravaggi A.
        • et al.
        Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.
        Clin Cancer Res. 2001; 7: 804s-810s
        • Holloway R.W.
        • Mehta R.S.
        • Finkler N.J.
        • et al.
        Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients.
        Gynecol Oncol. 2002; 87: 8-16
        • Santin A.D.
        • Zhan F.
        • Bellone S.
        • et al.
        Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy.
        Int J Cancer. 2004; 112: 14-25
        • Bignotti E.
        • Tassi R.A.
        • Calza S.
        • et al.
        Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy.
        Gynecol Oncol. 2006; 103: 405-416
        • Tsang K.Y.
        • Palena C.
        • Gulley J.
        • Arlen P.
        • Schlom J.
        A human cytotoxic T-lymphocyte epitope and its agonist epitope from the nonvariable number of tandem repeat sequence of MUC-1.
        Clin Cancer Res. 2004; 10: 2139-2149
        • Wierecky J.
        • Mueller M.
        • Brossart P.
        Dendritic cell-based cancer immunotherapy targeting MUC-1.
        Cancer Immunol Immunother. 2006; 55: 63-67
        • Schuler G.
        • Steinman R.M.
        Dendritic cells as adjuvants for immune-mediated resistance to tumors.
        J Exp Med. 1997; 186: 1183-1187
        • Banchereau J.
        • Steinman R.M.
        Dendritic cells and the control of immunity.
        Nature. 1998; 392: 245-252
        • Osada T.
        • Clay T.M.
        • Woo C.Y.
        • Morse M.A.
        • Lyerly H.K.
        Dendritic cell-based immunotherapy.
        Int Rev Immunol. 2006; 25: 377-413
        • Schultes B.C.
        • Whiteside T.L.
        Monitoring of immune responses to CA125 with an IFN-gamma ELISPOT assay.
        J Immunol Methods. 2003; 279: 1-15
        • Ge Q.
        • Rao V.P.
        • Cho B.K.
        • Eisen H.N.
        • Chen J.
        Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/MHC epitopes and strength of their interaction with T cell receptors.
        Proc Natl Acad Sci U S A. 2001; 98: 1728-1733
        • Valitutti S.
        • Muller S.
        • Dessing M.
        • Lanzavecchia A.
        Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy.
        J Exp Med. 1996; 183: 1917-1921
        • Zhang L.
        • Conejo-Garcia J.R.
        • Katsaros D.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N Engl J Med. 2003; 348: 203-213