Journal of the American College of Surgeons
Volume 210, Issue 2 , Pages 140-147 , February 2010

Clinical and Immunologic Responses of HLA-A3+ Breast Cancer Patients Vaccinated with the HER2/neu-Derived Peptide Vaccine, E75, in a Phase I/II Clinical Trial

  • Ritesh Patil, MD

      Affiliations

    • Joyce Murtha Breast Care Center, Windber Medical Center, Windber, PA
    • ,
  • Guy T. Clifton, MD

      Affiliations

    • Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX
    • ,
  • Jarrod P. Holmes, MD

      Affiliations

    • Department of Hematology and Medical Oncology, Naval Medical Center, San Diego, CA
    • ,
  • Asna Amin, MD

      Affiliations

    • Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
    • ,
  • Mark G. Carmichael, MD

      Affiliations

    • Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
    • ,
  • Jeremy D. Gates, MD

      Affiliations

    • Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX
    • ,
  • Linda H. Benavides, MD

      Affiliations

    • Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX
    • ,
  • Matthew T. Hueman, MD

      Affiliations

    • Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
    • ,
  • Sathibalan Ponniah, PhD

      Affiliations

    • Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
    • ,
  • George E. Peoples, MD, FACS

      Affiliations

    • Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX
    • Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
    • Corresponding Author InformationCorrespondence address: col George E Peoples, md, facs, Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX 78234

Received 26 August 2009 ,Revised 20 October 2009 ,Accepted 21 October 2009.

References 

  1. Pritchard KI, Shepherd LE, O'Malley FP, et al. National Cancer Institute of Canada Clinical Trials Group: HER2 and responsiveness of breast cancer to adjuvant therapy. N Engl J Med. 2006;354:2103–2111
  2. Anderson BW, Peoples GE, Murray JL, et al. Peptide priming of cytolytic activity to HER-2 epitope 369-377 in healthy individuals. Clin Cancer Res. 2000;6:4192–4200
  3. Zaks TZ, Rosenberg SA. 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. 1998;58:4902–4908
  4. Knutson KL, Schiffman K, Cheever MA, Disis ML. Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide p369-377, results in short-lived peptide-specific immunity. Clin Cancer Res. 2002;8:1014–1018
  5. Murray JL, Gillogly ME, Przepiorka D, et al. Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin Cancer Res. 2002;8:3407–3418
  6. Madjd Z, Spendlove I, Pinder SE, et al. Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. Int J Cancer. 2005;117:248–255
  7. Rolland P, Deen S, Scott I, et al. Human leukocyte antigen class I antigen expression is an independent prognosis factor in ovarian cancer. Clin Cancer Res. 2007;13:3591–3596
  8. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer. 2006;118:6–10
  9. Lee TD. Distribution of HLA antigens in North American caucasians, North American blacks and orientals. In:  Lee J editors. The HLA system. New York: Springer-Verlag; 1990;p. 154
  10. Alves PM, Viatte S, Fagerberg T, et al. Immunogenicity of the carcinoembryonic antigen derived peptide 694 in HLA-A2 healthy donors and colorectal carcinoma patients. Cancer Immunol Immunother. 2007;56:1795–1805
  11. Ras E, van der Burg SH, Zegveld ST, et al. Identification of potential HLA-A *0201 restricted CTL epitopes derived from the epithelial cell adhesion molecule (Ep-CAM) and the carcinoembryonic antigen (CEA). Hum Immunol. 1997;53:81–89
  12. Zhang HG, Chen HS, Peng JR, et al. Specific CD8(+)T cell responses to HLA-A2 restricted MAGE-A3 p271-279 peptide in hepatocellular carcinoma patients without vaccination. Cancer Immunol Immunother. 2007;56:1945–1954
  13. Dong HL, Li ZS, Ye J, et al. Identification of HLA-A2-restricted CTL epitope encoded by the MAGE-n gene of human hepatocellular carcinoma. Cancer Biol Ther. 2004;3:891–898
  14. Lustgarten J, Theobald M, Labadie C, et al. Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8. Hum Immunol. 1997;52:109–118
  15. Linehan DC, Goedegebuure PS, Peoples GE, et al. Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer. J Immunol. 1995;155:4486–4491
  16. Peoples GE, Goedegebuure PS, Andrews JV, et al. HLA-A2 presents shared tumor-associated antigens derived from endogenous proteins in ovarian cancer. J Immunol. 1993;151:5481–5491
  17. Darrow TL, Slingluff CL, Seigler HF. The role of HLA class I antigens in recognition of melanoma cells by tumor-specific cytotoxic T lymphocytes: evidence for shared tumor antigens. J Immunol. 1989;142:3329–3335
  18. Kono K, Rongcun Y, Charo J, et al. Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes. Int J Cancer. 1998;78:202–208
  19. Gourley C, Thornton C, Massie C, et al. Is there a relationship between HLA type and prognostic factors in breast cancer?. Anticancer Res. 2003;23:633–638
  20. Iaffaioli RV, Maio M, Ruggiero G, et al. HLA and prognostic factors in primary breast cancer. Int J Cancer. 1985;35:581–585
  21. Gamzatova Z, Villabona L, Dahlgren L, et al. Human leucocyte antigen (HLA) A2 as a negative clinical prognostic factor in patients with advanced ovarian cancer. Gynecol Oncol. 2006;103:145–150
  22. Peoples GE, Holmes JP, Hueman MT, et al. Combined clinical trial results of a HER-2/neu (ϵ75) vaccine for the prevention of recurrence in high risk breast cancer patients (United States Military Cancer Institute Clinical Trials Group Study. I-01 and I-02). Clin Cancer Res. 2008;14:797–803
  23. Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med. 1995;181:2109–2117
  24. Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994;152:163–175
  25. Rammensee HG, Bachmann J, Stevanovic S. MHC ligands and peptide motifs (Molecular Biology Intelligence Unit). New York: Springer; 1997;
  26. Sotiropoulou PA, Perez SA, Iliopoulou EG, et al. Cytotoxic T-cell precursor frequencies to HER-2 (369-377) in patients with HER-2/neu-positive epithelial tumors. Br J Cancer. 2003;89:1055–1061
  27. Hueman MT, Dehqanzada ZA, Novak TE, et al. Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients. Clin Cancer Res. 2005;11:7470–7479
  28. Woll MM, Fisher CM, Ryan GB, et al. Direct measurement of peptide-specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients. J Clin Immunol. 2004;24:449–461
  29. Jordan TJ, Sunderam G, Thomas L, Reichman LB. Tuberculin reaction size measurement by the pen method compared to traditional palpation. Chest. 1987;92:234–236
  30. Mittendorf EA, Holmes JP, Ponniah S, Peoples GE. The E75 HER2/neu peptide vaccine. Cancer Immunol Immunother. 2008;57:1511–1521
  31. Cibotti R, Kanellopoulos JM, Cabaniols JP, et al. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci USA. 1992;89:416–420
  32. Dols A, Meijer SL, Smith JW, et al. Allogeneic breast cancer cell vaccines. Clin Breast Cancer. 2003;3(Suppl 4):S173–S180
  33. Sherman LA, Burke TA, Biggs JA. Extracellular processing of peptide antigens that bind class I major histocompatibility molecules. J Exp Med. 1992;175:1221–1226
  34. Vitiello A, Potter TA, Sherman LA. The role of beta 2-microglobulin in peptide binding by class I molecules. Science. 1990;250:1423–1426
  35. Mittendorf EA, Gurney JM, Storrer CE, et al. Vaccination with a HER2/neu peptide induces intra- and inter-antigenic epitope spreading in patients with early stage breast cancer. Surgery. 2006;139:407–418
  36. Slingluff CL, Petroni GR, Chianese-Bullock KA, et al. Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res. 2007;13:6386–6395
  37. Holmes JP, Amin A, Storrer CE, et al. Clinical and immunologic effects of a HER2/neu (E75) peptide vaccine booster in previously vaccinated breast cancer patients. [abstract] J Clin Oncol ASCO Annu Meet Proc. 2007;25:3014
  38. Klarnet JP, Matis LA, Kern DE, et al. Antigen-driven T cell clones can proliferate in vivo, eradicate disseminated leukemia, and provide specific immunologic memory. J Immunol. 1987;138:4012–4017
  39. Disis ML, Grabstein KH, Sleath PR, Cheever MA. Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res. 1999;5:1289–1297
  40. Holmes JP, Benavides LC, Gates JD, et al. Results of the first phase I clinical trial of the novel Ii-key hybrid preventive HER2/neu peptide (AE37) vaccine. J Clin Oncol. 2008;26:3426–3433

 Disclosure Information: Dr Peoples holds patent rights to the E75 vaccine.

 This study was supported by the United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, and the Department of Clinical Investigation, Walter Reed Army Medical Center, Bethesda, MD.

 This article represents the personal viewpoint of the authors and cannot be construed as a statement of official Department of the Army, Department of the Navy, or Department of Defense policy.

PII: S1072-7515(09)01557-9

doi: 10.1016/j.jamcollsurg.2009.10.022

Journal of the American College of Surgeons
Volume 210, Issue 2 , Pages 140-147 , February 2010

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