Ii-Key/HER-2/neu MHC class-II antigenic epitope vaccine peptide for breast cancer.
OBJECTIVE
Cytotoxic T lymphocytes (CTL)- and T-helper cell-specific, and major histocompatibility complex (MHC) class-I and class-II peptides, respectively, of the HER-2/ neu protein, induce immune responses in patients. A major challenge in developing cancer peptide vaccines is breaking tolerance to tumor-associated antigens which are functionally self-proteins. An adequate CD4+ T-helper response is required for effective and lasting responses.


METHODS
Stimulating anti-cancer CD4+ T cell responses by MHC class-II epitope peptides has been limited by their weak potency, at least compared with tight-binding MHC class-I epitope peptides. Previously, a potent T-cell response to a MHC class-II epitope was engineered by coupling the N-terminus of the pigeon cytochrome C [PGCC(95-104)] MHC class-II epitope to the C-terminus of an immunoregulatory segment of the Ii protein (hIi77-81, the Ii-Key peptide) through a polymethylene spacer.


RESULTS
In vitro presentation of the MHC class-II epitope to a T hybridoma was enhanced greatly (>250 times). Now, an Ii-Key/HER-2/neu (777-789) MHC class-II epitope hybrid peptide stimulated lymphocytes from both a healthy donor and a patient with metastatic breast carcinoma. The in vitro primary stimulation with the hybrid peptide strongly activated IFN-gamma release, whereas the epitope-only peptide was weakly active. In fact, the hybrid stimulated IFN-gamma release as well as the wild-type peptide when augmented with IL-12; however, the hybrid was comparable to free peptide in stimulating IL-4 release. This pattern is consistent with preferential activation along a non-tolerogenic Th1 pathway.


CONCLUSIONS
Such Ii-Key/MHC class-II epitope hybrid peptides have both diagnostic and therapeutic applications.
Gillogly
Michael E
ME
M.D. Anderson Cancer Center, 1525 Holcombe Blvd., Houston, TX 77030, USA.
Kallinteris
Nikoletta L
NL
Xu
Minzhen
M
Gulfo
Joseph V
JV
Humphreys
Robert E
RE
Murray
James L
JL
D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D019496:Cancer Vaccines / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D022223:Vaccines, Subunit; C045084:invariant chain