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5-fluorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine.

AbstractBACKGROUND:
Thymidylate synthase (TS), a key enzyme in DNA synthesis, is often overexpressed in cancer cells. Some chemotherapeutic agents, such as 5-fluorouracil (5-FU), act by inhibiting TS expression. We evaluated whether a novel 28-amino acid multiepitope peptide, TS/PP, that contains the sequences of three TS-derived epitopes with binding motifs for HLA-A(*)02.01 could induce a TS-directed cytotoxic T-lymphocyte (CTL) response with antitumor activity.
METHODS:
TS/PP peptide immunologic activity in CTL lines derived from human leukocyte antigen (HLA)-A(*)02.01+ peripheral blood mononuclear cells (PBMCs) was tested in the presence of interleukin-2 and autologous TS/PP peptide-loaded dendritic cells. Immunologic and antitumor activities of TS/PP and its toxicity were also evaluated in vivo in HLA-A(*)02.01 transgenic (HHD) mice that were vaccinated with TS/PP, control, or TS-peptide cocktail and treated with or without 5-FU chemotherapy. The mice were also inoculated subcutaneously with TS-expressing EL-4/HHD lymphoma cells to assess immune response against these tumor cells.
RESULTS:
TS/PP-specific CTL lines showed a TS-multiepitopic specificity and were able to kill TS+/HLA-A(*)02.01+ breast and colon carcinoma cells. The killing ability against target cells previously exposed to sublethal doses of 5-FU was statistically significantly greater than against untreated target cells (43.5% versus 26.5% at 25/1 effector to target ratio [Difference {diff} = 17.0]; 95% confidence interval [CI] = 12.6 to 20.4) for MDA-MB-231 breast carcinoma cells and 73.5 versus 48.5 (diff = 25.0; 95% CI = 16.2 to 33.8) for the SW-1463 colon carcinoma cells. HHD mice vaccinated with TS/PP manifested a TS-peptide-specific CTL response with no sign of autoimmunity or toxicity. Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS+)EL-4/HHD lymphoma cells.
CONCLUSIONS:
The multiepitopic TS/PP vaccine induces a tumor-specific immune response in mice and is especially potent when used in combination with 5-FU-based chemotherapy.
AuthorsPierpaolo Correale, Maria Teresa Del Vecchio, Giuseppa Di Genova, Gianni Gori Savellini, Marco La Placa, Chiara Terrosi, Marzio Vestri, Renato Urso, Francois Lemonnier, Angelo Aquino, Enzo Bonmassar, Giorgio Giorgi, Guido Francini, Maria Grazia Cusi
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 97 Issue 19 Pg. 1437-45 (Oct 05 2005) ISSN: 1460-2105 [Electronic] United States
PMID16204693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • Peptides
  • Thymidylate Synthase
  • Fluorouracil
Topics
  • Animals
  • Antimetabolites, Antineoplastic (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Breast Neoplasms (drug therapy)
  • Cancer Vaccines (immunology, pharmacology)
  • Carcinoma (drug therapy)
  • Cell Culture Techniques
  • Colonic Neoplasms (drug therapy)
  • Cytotoxicity, Immunologic (drug effects)
  • Dendritic Cells
  • Epitopes, T-Lymphocyte (pharmacology)
  • Female
  • Flow Cytometry
  • Fluorouracil (pharmacology)
  • HLA-A Antigens
  • Humans
  • Immunohistochemistry
  • Lymphoma (drug therapy)
  • Mice
  • Mice, Transgenic
  • Peptides (pharmacology)
  • T-Lymphocytes, Cytotoxic (drug effects, immunology)
  • Thymidylate Synthase (metabolism)
  • Transfection
  • Transplantation, Isogeneic

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