Cancer Immunology, Immunotherapy

, Volume 59, Issue 8, pp 1211–1221 | Cite as

Antitumor cytotoxic T-cell response induced by a survivin peptide mimic

  • Michael J. Ciesielski
  • Manmeet S. Ahluwalia
  • Stephan A. Munich
  • Molly Orton
  • Tara Barone
  • Asher Chanan-Khan
  • Robert A. Fenstermaker
Original Article


Survivin is a tumor-associated antigen with significant potential as a cancer vaccine target. We have identified a survivin peptide mimic containing human MHC class I epitopes and a potential class II ligand that induces a potent antitumor response in C57BL/6 mice with GL261 cerebral gliomas. This peptide is able to elicit both CD8+ CTL and T helper cell responses in C57BL/6 mice. The corresponding region of the human survivin molecule represented by peptide SVN53-67 is 100% homologous to the murine protein, but SVN53-67 is weakly immunogenic in man. We evaluated several amino acid substitutions in putative human MHC I anchor positions in SVN53-67 to identify potential peptide mimics that could provide an enhanced antitumor immune response against human glioma and primary central nervous system lymphoma (PCNSL) cells in culture. We evaluated survivin peptides with predicted binding to human HLA-A*0201 antigen using peptide-loaded dendritic cells from PBMC of patients with these malignancies. One alteration (M57) led to binding to HLA-A*0201 with significantly higher affinity. We compared the ability of autologous dendritic cells loaded with SVN53-67 peptide and SVN53-67/M57 in CTL assays against allomatched and autologous, survivin-expressing, human malignant glioma and PCNSL cells. Both SVN53-67 and SVN53-67/M57 produced CTL-mediated killing of malignant target cells; however, SVN53-67/M57 was significantly more effective than SVN53-67. Thus, SVN53-67/M57 may act as a peptide mimic to induce an enhanced antitumor CTL response in tumor patients. The use of SVN53-67/M57 as a cancer vaccine might have application for cancer vaccine therapy.


Antigen Glioma Peptide Survivin Tumor Vaccine 



This work was supported by NIH 5R21 NS049309-02 (RAF), NIH 5P30 CA16056-29, the Linda Scime Fund of the Roswell Park Alliance Foundation, and the Glioblastoma Multiforme Grant awarded to MJC by the National Brain Tumor Foundation.


  1. 1.
    Conway EM, Pollefeyt S, Cornelissen J, DeBaere I, Steiner-Mosonyi M, Ong K, Baens M, Collen D, Schuh AC (2000) Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions. Blood 95:1435–1442PubMedGoogle Scholar
  2. 2.
    Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A (2000) High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 19:617–623CrossRefPubMedGoogle Scholar
  3. 3.
    Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH (2001) An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40:1117–1123CrossRefPubMedGoogle Scholar
  4. 4.
    Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri DC (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43–49PubMedGoogle Scholar
  5. 5.
    Ciesielski MJ, Apfel L, Barone TA, Castro CA, Weiss TC, Fenstermaker RA (2006) Antitumor effects of a xenogeneic survivin bone marrow derived dendritic cell vaccine against murine GL261 gliomas. Cancer Immunol Immunother 55:1491–1503CrossRefPubMedGoogle Scholar
  6. 6.
    Chakravarti A, Noll E, Black PM et al (2002) Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20:1063–1068CrossRefPubMedGoogle Scholar
  7. 7.
    Kajiwara Y, Yamasaki F, Hama S et al (2003) Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97:1077–1083CrossRefPubMedGoogle Scholar
  8. 8.
    Rohayem J, Diestelkoetter P, Weigle B et al (2000) Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients. Cancer Res 60:1815–1817PubMedGoogle Scholar
  9. 9.
    Ciesielski MJ, Kozbor D, Castanaro CA, Barone TA, Fenstermaker RA (2008) Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma. Cancer Immunol Immunother 57:1827–1835CrossRefPubMedGoogle Scholar
  10. 10.
    Seshadri M, Ciesielski M (2009) MRI-based characterization of vascular disruption by 5, 6-dimethylxanthenone-4-acetic acid in gliomas. J Cereb Blood Flow Metab 29:1373–1382CrossRefPubMedGoogle Scholar
  11. 11.
    Rammensee HG, Bachmann J, Emmerich NN, Bachor OA, Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219CrossRefPubMedGoogle Scholar
  12. 12.
    Dionne SO et al (2003) Functional characterization of CTL against gp100 altered peptide ligands. Cancer Immunol Immunother 52:199–206PubMedGoogle Scholar
  13. 13.
    Krajewska M, Krajewski S, Banares S et al (2003) Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res 9:4914–4925PubMedGoogle Scholar
  14. 14.
    Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I (2002) Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett 184:105–116CrossRefPubMedGoogle Scholar
  15. 15.
    Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I (2002) Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma. Int J Mol Med 10:211–216PubMedGoogle Scholar
  16. 16.
    Yamashita S, Masuda Y, Kurizaki T et al (2007) Survivin expression predicts early recurrence in early-stage breast cancer. Anticancer Res 27:2803–2808PubMedGoogle Scholar
  17. 17.
    Andersen MH, Svane IM, Becker JC, Straten PT (2007) The universal character of the tumor-associated antigen survivin. Clin Cancer Res 13:5991–5994CrossRefPubMedGoogle Scholar
  18. 18.
    Oto OA, Paydas S, Tanriverdi K, Seydaoglu G, Yavuz S, Disel U (2007) Survivin and EPR-1 expression in acute leukemias: prognostic significance and review of the literature. Leuk Res 31:1495–1501CrossRefPubMedGoogle Scholar
  19. 19.
    Andersen MH, Pedersen LO, Capeller B, Brocker EB, Becker JC, thor Straten P (2001) Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res 61:5964–5968PubMedGoogle Scholar
  20. 20.
    Hadrup SR, Gehl J, Sorensen RB, Geertsen PF, Straten PT, Andersen MH (2006) Persistence of survivin specific T cells for seven years in a melanoma patient during complete remission. Cancer Biol Ther 5:480–482PubMedCrossRefGoogle Scholar
  21. 21.
    Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54CrossRefPubMedGoogle Scholar
  22. 22.
    Overwijk WW, Restifo NP (2000) Autoimmunity and the immunotherapy of cancer: targeting the “self” to destroy the “other”. Crit Rev Immunol 20:433–450PubMedGoogle Scholar
  23. 23.
    Lohr J, Knoechel B, Nagabhushanam V, Abbas AK (2005) T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens. Immunol Rev 204:116–127CrossRefPubMedGoogle Scholar
  24. 24.
    Fikes JD, Sette A (2003) Design of multi-epitope, analogue-based cancer vaccines. Expert Opin Biol Ther 3:985–993CrossRefPubMedGoogle Scholar
  25. 25.
    Guevara-Patino JA, Turk MJ, Wolchok JD, Houghton AN (2003) Immunity to cancer through immune recognition of altered self: studies with melanoma. Adv Cancer Res 90:157–177CrossRefPubMedGoogle Scholar
  26. 26.
    Trojan A, Witzens M, Schultze JL et al (2001) Generation of cytotoxic T lymphocytes against native and altered peptides of human leukocyte antigen-A*0201 restricted epitopes from the human epithelial cell adhesion molecule. Cancer Res 61:4761–4765PubMedGoogle Scholar
  27. 27.
    Keogh E, Fikes J, Southwood S, Celis E, Chesnut R, Sette A (2001) Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. J Immunol 167:787–796PubMedGoogle Scholar
  28. 28.
    Valmori D, Fonteneau JF, Lizana CM et al (1998) Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues. J Immunol 160:1750–1758PubMedGoogle Scholar
  29. 29.
    Parkhurst MR, Salgaller ML, Southwood S et al (1996) Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. J Immunol 157:2539–2548PubMedGoogle Scholar
  30. 30.
    Evavold BD, Sloan-Lancaster J, Allen PM (1993) Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today 14:602–609CrossRefPubMedGoogle Scholar
  31. 31.
    Loftus DJ, Squarcina P, Nielsen MB et al (1998) Peptides derived from self-proteins as partial agonists and antagonists of human CD8+ T-cell clones reactive to melanoma/melanocyte epitope MART1(27-35). Cancer Res 58:2433–2439PubMedGoogle Scholar
  32. 32.
    Tynan FE, Burrows SR, Buckle AM et al (2005) T cell receptor recognition of a ‘super-bulged’ major histocompatibility complex class I-bound peptide. Nat Immunol 6:1114–1122CrossRefPubMedGoogle Scholar
  33. 33.
    Tynan FE, Reid HH, Kjer-Nielsen L et al (2007) A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nat Immunol 8:268–276CrossRefPubMedGoogle Scholar
  34. 34.
    Pardoll DM (1999) Inducing autoimmune disease to treat cancer. Proc Natl Acad Sci USA 96:5340–5342CrossRefPubMedGoogle Scholar
  35. 35.
    Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 188:2357–2368CrossRefPubMedGoogle Scholar
  36. 36.
    Kim W, Liau LM (2010) Dendritic cell vaccines for brain tumors. Neurosurg Clin N Am 21:139–157CrossRefPubMedGoogle Scholar
  37. 37.
    Wheeler CJ, Black KL (2009) DCVax-Brain and DC vaccines in the treatment of GBM. Expert Opin Investig Drugs 18:509–519CrossRefPubMedGoogle Scholar
  38. 38.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8:2773–2779CrossRefPubMedGoogle Scholar
  39. 39.
    Heimberger AB, Sampson JH (2009) The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther 9:1087–1098CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Michael J. Ciesielski
    • 1
    • 2
  • Manmeet S. Ahluwalia
    • 3
  • Stephan A. Munich
    • 1
  • Molly Orton
    • 1
  • Tara Barone
    • 1
  • Asher Chanan-Khan
    • 2
    • 3
  • Robert A. Fenstermaker
    • 1
    • 2
  1. 1.Department of NeurosurgeryRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of ImmunologyRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA

Personalised recommendations