Abstract
Carcinoembryonic antigen (CEA) is strongly expressed in a vast majority of gastrointestinal carcinomas. Recently, epitope peptides of CEA were identified. We have demonstrated HLA-A24–restricted peptide, CEA652[9] (TYACFVSNL), was capable of eliciting specific cytotoxic T lymphocytes (CTLs) which could lyse tumor cells expressing HLA-A24 and CEA. HLA-A24 is the most applicable MHC class I allele in the Japanese population. In this pilot study, we have used the peptide-pulsed dendritic cells (DCs) generated from peripheral blood mononuclear cells (PBMCs) supplemented with GM-CSF and IL-4 as the source of the vaccine. Eight patients with advanced CEA-expressing gastrointestinal malignancies received subcutaneous injections every 2 or 3 weeks. Immunomonitoring was performed by ELISpot (enzyme-linked immunosorbent spot) assay to measure the precursor frequency of CTLs and their capacity to elicit antitumor CTLs in vitro. Four of seven patients have developed their CTL response after vaccinations. DTH reaction was observed in one of eight patients at the DC-injected site. Skin biopsy at the injected site showed the infiltration of the lymphocytes. Furthermore, A24/CEA peptide tetramer assay revealed an increase in peptide-specific T-cell precursor frequency in vaccinated patients. No significant toxic adverse effects were observed, except for mild diarrhea in one case after three vaccinations. Three patients have shown stabilization of the disease after vaccinations. In conclusion, our results clearly demonstrated that our vaccination protocol was safe and might develop a CEA-specific CTL response in cancer patients.
Similar content being viewed by others
References
Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K,Stanners CP (1989) Carcinoembryonic antigen, a human tumor marker, functions as an intracellular adhesion molecule. Cell 57:327
Thompson JA (1995) Molecular cloning and expression of carcinoembryonic antigen gene family members. Tumor Biol 16:10
Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, Schlom J (1995) Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J Natl Cancer Inst 87:982
Marshall JL, Hawkins MJ, Tsang KY, Richond E, Pedicano JE, Zhu M, Schlom J (1999) Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that express human carcinoembryonic antigen. J Clin Oncol 17:332
Kawashima I, Hudson SJ, Tsai V, Southwood S, Takesako K, Appella E, Sette A, Celis E (1998) The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. Hum Immunol 59:1
Kawashima I, Tsai V, Southwood S, Takesako K, Sette A, Celis E (1999) Identification of HLA-A3-restricted cytotoxic T lymphocyte epitopes from carcinoembryonic antigen and HER-2/neu by primary in vitro immunization with peptide-pulsed dendritic cells. Cancer Res 59:431
Nukaya I, Yasumoto M, Iwasaki T, Ideno M, Sette A, Celis E, Takesako K, Kato I (1999) Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer 80:92
Celluzzi CM, Mayordomo JI, Storkus WJ, Lotze MT, Falo D Jr (1996) Peptide-pulsed dendritic cells induce antigen-specific, CTL mediated protective tumor immunity. J Exp Med 183:283
Banchereau J, Steinman RT (1998) Dendritic cells and the control of immunity. Nature 392:254
Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacker B, Konwalkinka G, Fritsch PO, Steinman RM, Schuler G (1994) Proliferating dendritic cell progenitors in human blood. J Exp Med 180:83
Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D (1998) Vaccination of melanoma patients with peptide-or tumor lysate-pulsed dendritic cells. Nat Med 4:328
Thurner B, Haendle I, Roder C, Dickmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, Driesch P, Brocker EB, Steinman RM, Enk A, Kampgen E, Schuler G (1999) Vaccination with Mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cell and induces regression of some metastasis in advanced stage IV melanoma. J Exp Med 190:1669
Nair SK, Hull S, Coleman D, Gilboa E, Lyerly HM, Morse MA (1999) Induction of carcinoembryonic antigen (CEA)-specific cytotoxic T-lymphocyte responses in vitro using autologous dendritic cells loaded with CEA peptide or CEA RNA in patients with metastatic malignancies expressing CEA. Int J Cancer 82:121
Morse MA, Deng Y, Colemn D, Hull S, Kitrell-Fisher E, Nair S, Schlom J, Ryback M, Lyerly HM (1999) A phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin Cancer Res 5:1331
Salgaller ML, Lodge H, Kenny GM, Rogers M, Boynton AL, Murphy, G.P. (1998) Report of immune monitoring of prostate cancer patients undergoing T cell therapy using dendritic cells pulsed with HLA-A2-specific peptides from prostate-specific membrane antigen (PSMA). Prostate 35:144
Holtl L, Rieser C, Papesh C, Ramoner R, Herold M, Klocker H, Radmayr C, Stenzl A, Bartsch G, Thurnher M (1999) Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells. J Urol 161:777
Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG Levy R (1996) Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52
Dhodapkar MV, Steinman RM, Sapp M, Desai, H, Fosella C, Krasovsky J, Donahoe SM, Dunbar PR, Cerundolo V, Nixon DF, Bhardwaj N (1999) Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J Clin Invest 104:173
Tsai V, Southwood S, Sidney J, Sakaguchi K, Kawakami Y, Appella E, Sette A, Celis E (1997) Identification of subdominant CTL epitopes of the gp100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol 158:1796
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038
Altman JD, Moss PAH, Goulder PJR, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM,Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wundrlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321
Zaks TZ, Rosenberg SA (1998) Immunization with a peptide epitope (p369–377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. Cancer Res 58:4902
Xueyou H, Chakraborty G, Sporn JR, Kurtzman SH, Ergin MT, Mukherji B (1996) Enhancement of cytotoxic T lymphocyte precursor frequency in melanoma patients following immunization with the MAGE-1 peptide loaded antigen presenting cell-based vaccine. Cancer Res 56:2479
Jager E, Bernhard H, Romero P, Ringhoffer M, Arand M, Karbach J, Ileemann C, Hagedorn M, Knuth A (1996) Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: implications for tumor vaccines with melanoma-associated antigens. Int. J. Cancer 66:162
Pass HA, Schwarz SL, Wunderlich JR, Rosenberg SA (1998) Immunization of patients with melanoma peptide vaccines: immunologic assessment using ELISPOT assay. Cancer J Sci Am 4:316
Lee PP, Yee C, Savage, PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677
Marchand M, Baren N, Weynants P, Brichard V, Dreno B, Tessier MH, Rankin E, Parmiani G, Arienti F, Humblet Y, Bourlond A, Vanwijck R, Lienard D, Beaudin M, Dietrich PY, Russo V, Kerger J, Masucci G, Jager E, Greve J, Atzpodien J, Braseur F, Coulie PG, Bruggen P, Boon T (1999) Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 80:219
Lee KH, Wang E, Nielsen MB, Wunderlich J, Migueles S, Connor M, Steinberg SM, Rosenberg SA, Marincola FM (1999) Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility in vitro stimulation but does not lead to tumor regression. J Immunol 163:6292
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwe P, Marincola FM, Topalian SL, Restifo NP, Sznol M, Schwarz L, Spiess PJ, Wunderlich JR, Sipp CA, Einhorn JH, Rogers-Freezer L, White DE (1999) Impact of cytokine administration of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J Immunol 163:1690
Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Carbello F, Stern PL (1993) Natural history of HLA expression during tumour development. Immunol Today 14:491
Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerotii J-C, Tschopp J (1996) Melanoma cell expression of (Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363
Wang F, Bade E, Kuniyoshi C, Spears L, Jefrey G, Marty V, Groshen S, Weber J (1999) Phase I trial of a MART-1 peptide vaccine with incomplete Freund’s adjuvant for resected high-risk melanoma. Clin Cancer Res 5:2756
Shimizu K, Fields RC, Giedlin M, Mule JJ (1999) Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. Proc Natl Acad Sci U S A 96:2268
Tanaka H, Tsunoda T, Nukaya I, Sette A, Matsuda K, Umano Y, Yamaue H, Takesako K, Tanimura H (2001) Mapping the HLA-A24-restricted T-cell epitope from a tumour-associated antigen HER2/neu: possible immunotherapy for colorectal carcinoma. Br J Cancer 84:94
Umano Y, Tsunoda T, Tanaka H, Matsuda K, Yamaue H, Tanimura H (2002) Generation of cytotoxic T cell response to an HLA-A24 epitope peptide derived from wild-type p53. Br J Cancer 97:83
Acknowledgements
This study was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan (No. 09671245).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Matsuda, K., Tsunoda, T., Tanaka, H. et al. Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide–pulsed dendritic cells. Cancer Immunol Immunother 53, 609–616 (2004). https://doi.org/10.1007/s00262-003-0491-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-003-0491-7