Skip to main content

Advertisement

SpringerLink
Log in

Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Yeast-CEA (GI-6207) is a therapeutic cancer vaccine genetically modified to express recombinant carcinoembryonic antigen (CEA) protein, using heat-killed yeast (Saccharomyces cerevisiae) as a vector. In preclinical studies, yeast-CEA induced a strong immune response to CEA and antitumor responses. Patients received subcutaneous vaccines every 2 weeks for 3 months and then monthly. Patients were enrolled at 3 sequential dose levels: 4, 16, and 40 yeast units (107 yeast particles/unit). Eligible patients were required to have serum CEA > 5 ng/mL or > 20 % CEA+ tumor block, ECOG PS 0–2, and no history of autoimmunity. Restaging scans were performed at 3 months and then bimonthly. Peripheral blood was collected for the analysis of immune response (e.g., by ELISPOT assay). Twenty-five patients with metastatic CEA-expressing carcinomas were enrolled. Median patient age was 52 (range 39–81). A total of 135 vaccines were administered. The vaccine was well tolerated, and the most common adverse event was grade 1/2 injection-site reaction. Five patients had stable disease beyond 3 months (range 3.5–18 months), and each had CEA stabilization while on-study. Some patients showed evidence post-vaccination of increases in antigen-specific CD8+ T cells and CD4+ T lymphocytes and decreases in regulatory T cells. Of note, a patient with medullary thyroid cancer had substantial T cell responses and a vigorous inflammatory reaction at sites of metastatic disease. Yeast-CEA vaccination had minimal toxicity and induced some antigen-specific T cell responses and CEA stabilization in a heterogeneous, heavily pre-treated patient population. Further studies are required to determine the clinical benefit of yeast-CEA vaccination.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Madan RA, Bilusic M, Heery C, Schlom J, Gulley JL (2012) Clinical evaluation of TRICOM vector therapeutic cancer vaccines. Semin Oncol 39(3):296–304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Guadagni F, Roselli M, Cosimelli M, Spila A, Cavaliere F, Arcuri R, D’Alessandro R, Fracasso PL, Casale V, Vecchione A, Casciani CU, Greiner JW, Schlom J (1997) Quantitative analysis of CEA expression in colorectal adenocarcinoma and serum: lack of correlation. Int J Cancer 72(6):949–954

    Article  CAS  PubMed  Google Scholar 

  3. Kass ES, Greiner JW, Kantor JA, Tsang KY, Guadagni F, Chen Z, Clark B, De Pascalis R, Schlom J, Van Waes C (2002) Carcinoembryonic antigen as a target for specific antitumor immunotherapy of head and neck cancer. Cancer Res 62(17):5049–5057

    CAS  PubMed  Google Scholar 

  4. Robbins PF, Eggensperger D, Qi CF, Schlom J (1993) Definition of the expression of the human carcinoembryonic antigen and non-specific cross-reacting antigen in human breast and lung carcinomas. Int J Cancer 53(6):892–897

    Article  CAS  PubMed  Google Scholar 

  5. Abdul-Wahid A, Huang EH, Lu H, Flanagan J, Mallick AI, Gariepy J (2012) A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo. Int J Cancer 131(12):2839–2851

    Article  CAS  PubMed  Google Scholar 

  6. Lee YJ, Han SR, Kim NY, Lee SH, Jeong JS, Lee SW (2012) An RNA aptamer that binds carcinoembryonic antigen inhibits hepatic metastasis of colon cancer cells in mice. Gastroenterology 143(1):155–165. e8

    Article  CAS  PubMed  Google Scholar 

  7. Li D, Hua S, Fan Y, Xu S, Duan X, Liu L, Che Y, Li S, Tan Y (2011) DNA vaccine expressing repeated carcinoembryonic antigen (CEA)(625–667) induces strong immunity in mice. Immunol Lett 135(1–2):124–128

    Article  CAS  PubMed  Google Scholar 

  8. Taheri M, Saragovi U, Fuks A, Makkerh J, Mort J, Stanners CP (2000) Self recognition in the Ig superfamily. Identification of precise subdomains in carcinoembryonic antigen required for intercellular adhesion. J Biol Chem 275(35):26935–26943

    CAS  PubMed  Google Scholar 

  9. Thompson JA, Grunert F, Zimmermann W (1991) Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J Clin Lab Anal 5(5):344–366

    Article  CAS  PubMed  Google Scholar 

  10. Zheng C, Feng J, Lu D, Wang P, Xing S, Coll JL, Yang D, Yan X (2011) A novel anti-CEACAM5 monoclonal antibody, CC4, suppresses colorectal tumor growth and enhances NK cells-mediated tumor immunity. PLoS ONE 6(6):e21146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A 98(15):8809–8814

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, Remondo C, Cereda V, Jones JL, Pazdur MP, Higgins JP, Hodge JW, Steinberg SM, Kotz H, Dahut WL, Schlom J (2008) Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res 14(10):3060–3069

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lesterhuis WJ, De Vries IJ, Schreibelt G, Schuurhuis DH, Aarntzen EH, De Boer A, Scharenborg NM, Van De Rakt M, Hesselink EJ, Figdor CG, Adema GJ, Punt CJ (2010) Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients. Anticancer Res 30(12):5091–5097

    PubMed  Google Scholar 

  14. Marshall JL, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwu L, Park S, Panicali D, Schlom J (2005) 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 23(4):720–731

    Article  CAS  PubMed  Google Scholar 

  15. Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL (2011) A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clin Cancer Res 17(22):7164–7173

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J (1999) A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res 59(22):5800–5807

    CAS  PubMed  Google Scholar 

  17. 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(13):982–990

    Article  CAS  PubMed  Google Scholar 

  18. Franzusoff A, Duke RC, King TH, Lu Y, Rodell TC (2005) Yeasts encoding tumour antigens in cancer immunotherapy. Expert Opin Biol Ther 5(4):565–575

    Article  CAS  PubMed  Google Scholar 

  19. Haller AA, Lauer GM, King TH, Kemmler C, Fiolkoski V, Lu Y, Bellgrau D, Rodell TC, Apelian D, Franzusoff A, Duke RC (2007) Whole recombinant yeast-based immunotherapy induces potent T cell responses targeting HCV NS3 and Core proteins. Vaccine 25(8):1452–1463

    Article  CAS  PubMed  Google Scholar 

  20. Stubbs AC, Wilson CC (2002) Recombinant yeast as a vaccine vector for the induction of cytotoxic T-lymphocyte responses. Curr Opin Mol Ther 4(1):35–40

    CAS  PubMed  Google Scholar 

  21. Bernstein MB, Chakraborty M, Wansley EK, Guo Z, Franzusoff A, Mostbock S, Sabzevari H, Schlom J, Hodge JW (2008) Recombinant Saccharomyces cerevisiae (yeast-CEA) as a potent activator of murine dendritic cells. Vaccine 26(4):509–521

    Article  CAS  PubMed  Google Scholar 

  22. Wansley EK, Chakraborty M, Hance KW, Bernstein MB, Boehm AL, Guo Z, Quick D, Franzusoff A, Greiner JW, Schlom J, Hodge JW (2008) Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clin Cancer Res 14(13):4316–4325

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Remondo C, Cereda V, Mostbock S, Sabzevari H, Franzusoff A, Schlom J, Tsang KY (2009) Human dendritic cell maturation and activation by a heat-killed recombinant yeast (Saccharomyces cerevisiae) vector encoding carcinoembryonic antigen. Vaccine 27(7):987–994

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Stubbs AC, Martin KS, Coeshott C, Skaates SV, Kuritzkes DR, Bellgrau D, Franzusoff A, Duke RC, Wilson CC (2001) Whole recombinant yeast vaccine activates dendritic cells and elicits protective cell-mediated immunity. Nat Med 7(5):625–629

    Article  CAS  PubMed  Google Scholar 

  25. Richards D, Muscarella P, Ritch P, Fisher W, Flynn P, Whiting S, Mathisen A, Ferrero J, Speyer S, Cohn A (2010) A randomized phase II adjuvant trial of resected patients with ras mutation bearing pancreas cancer treated with GI-4000 and gemcitabine or gemcitabine alone: a safety analysis of the first 100 treated patients. ASCO Gastrointestinal Cancers Symposium abstr 229

  26. Richards D, Muscarella P, Bekaii-Saab T, Wilfong L, Rosemurgy A, Ross S, Raynov J, Flynn P, Fisher W, Whiting S, Timcheva C, Harrell F, Mercaldo N, Kosten S, Speyer S, Richman J, Coeshott C, Cohn A, Ferraro J, Rodell TC, Apelian D (2012) A phase II adjuvant trial of GI-4000 plus gemcitabine versus gemcitabine alone in ras + patients with resected pancreas cancer: R1 subgroup analysis. Ann Oncol 23(supp 4)abstr 0002

    Google Scholar 

  27. Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, Dahut W (2006) A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 12(4):1260–1269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Britten CM, Meyer RG, Kreer T, Drexler I, Wolfel T, Herr W (2002) The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8(+) T lymphocytes in IFN-gamma ELISPOT assays. J Immunol Methods 259(1–2):95–110

    Article  CAS  PubMed  Google Scholar 

  29. Barnd DL, Lan MS, Metzgar RS, Finn OJ (1989) Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A 86(18):7159–7163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, Baranova AV, Kozlov AP, Schlom J (2007) The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy. Clin Cancer Res 13(8):2471–2478

    Article  CAS  PubMed  Google Scholar 

  31. Vergati M, Cereda V, Madan RA, Gulley JL, Huen NY, Rogers CJ, Hance KW, Arlen PM, Schlom J, Tsang KY (2011) Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination. Cancer Immunol Immunother 60(2):197–206

    Article  PubMed Central  PubMed  Google Scholar 

  32. Patel PH, Kockler DR (2008) Sipuleucel-T: a vaccine for metastatic, asymptomatic, androgen-independent prostate cancer. Ann Pharmacother 42(1):91–98

    Article  PubMed  Google Scholar 

  33. Longo DL (2010) New therapies for castration-resistant prostate cancer. N Engl J Med 363(5):479–481

    Article  CAS  PubMed  Google Scholar 

  34. von Mehren M, Arlen P, Gulley J, Rogatko A, Cooper HS, Meropol NJ, Alpaugh RK, Davey M, McLaughlin S, Beard MT, Tsang KY, Schlom J, Weiner LM (2001) 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 7(5):1181–1191

    Google Scholar 

  35. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422

    Article  CAS  PubMed  Google Scholar 

  37. Muller AJ, Prendergast GC (2007) Indoleamine 2,3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets 7(1):31–40

    Article  CAS  PubMed  Google Scholar 

  38. Teicher BA (2007) Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 13(21):6247–6251

    Article  CAS  PubMed  Google Scholar 

  39. Hattrup CL, Gendler SJ (2006) MUC1 alters oncogenic events and transcription in human breast cancer cells. Breast Cancer Res 8(4):R37

    Article  PubMed Central  PubMed  Google Scholar 

  40. Disis ML, Goodell V, Schiffman K, Knutson KL (2004) Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol 24(5):571–578

    Article  CAS  PubMed  Google Scholar 

  41. Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang KY, Yokokawa J, Hodge JW, Menard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, Dahut W (2005) Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11(9):3353–3362

    Article  CAS  PubMed  Google Scholar 

  42. Kudo-Saito C, Schlom J, Hodge JW (2005) Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses. Clin Cancer Res 11(6):2416–2426

    Article  CAS  PubMed  Google Scholar 

  43. Momita S, Ikeda S, Amagasaki T, Soda H, Yamada Y, Kamihira S, Tomonaga M, Kinoshita K, Ichimaru M (1990) Survey of anti-human T-cell leukemia virus type I antibody in family members of patients with adult T-cell leukemia. Jpn J Cancer Res 81(9):884–889

    Article  CAS  PubMed  Google Scholar 

  44. Goldstein MJ, Mitchell EP (2005) Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 23(4):338–351

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Diane J. Poole for her technical assistance and Zhimin Guo, who was involved in early preclinical development of the vaccine. The authors also thank Bonnie L. Casey and Debra Weingarten for their editorial assistance in the preparation of this manuscript.

Conflict of interest

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Marijo Bilusic, Philip M. Arlen, James L. Gulley & Ravi A. Madan

  2. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, MSC 1750, Bethesda, MD, 20892, USA

    Christopher R. Heery, Philip M. Arlen, Myrna Rauckhorst, Kwong Y. Tsang, Jo A. Tucker, Caroline Jochems, Jeffrey Schlom, James L. Gulley & Ravi A. Madan

  3. GlobeImmune Inc., Louisville, CO, USA

    David Apelian

Authors
  1. Marijo Bilusic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher R. Heery
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip M. Arlen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Myrna Rauckhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Apelian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwong Y. Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jo A. Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Caroline Jochems
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey Schlom
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. James L. Gulley
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ravi A. Madan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James L. Gulley.

Additional information

James L. Gulley and Ravi A. Madan have contributed equally to this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 148 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bilusic, M., Heery, C.R., Arlen, P.M. et al. Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma. Cancer Immunol Immunother 63, 225–234 (2014). https://doi.org/10.1007/s00262-013-1505-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-013-1505-8

Keywords

Search

Navigation