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.
To determine the toxicity and immunogenicity of the HER-2/neu, HLA-A2-restricted peptide E75 in patients with metastatic breast and ovarian cancer, 14 patients were vaccinated with escalating amounts of E75 (100, 500, and 1000 microg) mixed with 250 microg granulocyte macrophage colony-stimulating factor as adjuvant. Each vaccine dose was administered in a total volume of 1.5 ml divided into four intradermal injections and administered weekly for 4 weeks, followed by monthly boosts for a total of 10 injections. Vaccinations were well tolerated without significant toxicity. Blood was drawn before, at 8 weeks, and up to 13-16 months after vaccination for measurement of cellular immunity. Seven of 8 patients tested had significant delayed type hypersensitivity to E75 defined as >5 mm induration. Peripheral blood mononuclear cells from 5 of 9 patients tested proliferated to E75 with a stimulation index of > or = 2.0. Of 8 vaccinated patients tested for induction of a CTL response, 4 responded to stimulation by autologous dendritic cells plus cytokines by eliciting E75-specific lytic activity consistent with the presence of activated/memory cells, 2 others after in vitro stimulation with E75 + interleukin-12 +/- anti-CD152(33KD), whereas 2 others did not respond. Four patients with E75-specific CTLs present specifically recognized E75 on indicator tumors as demonstrated by cold-target inhibition of tumor lysis. These 4 patients showed E75-specific IFN-gamma production. peripheral blood mononuclear cell from 3 of these patients proliferated to E75, but stimulation indices were higher in the prevaccine samples. All 4 of the patients showed DTH responses to E75. These results demonstrate that vaccination with E75+ granulocyte macrophage colony-stimulating factor can induce both peptide-specific IFN-gamma and epitope specific CTLs, which lyse HER-2/neu+ tumors in stage IV patients.
Murray
James L
JL
Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Gillogly
Michael E
ME
Przepiorka
Donna
D
Brewer
Hannah
H
Ibrahim
Nuhad K
NK
Booser
Daniel J
DJ
Hortobagyi
Gabriel N
GN
Kudelka
Andrzej P
AP
Grabstein
Kenneth H
KH
Cheever
Martin A
MA
Ioannides
Constantin G
CG
D000069594:Abatacept; D000328:Adult; D000368:Aged; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D002455:Cell Division; D000939:Epitopes; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D015789:HLA-A2 Antigen / Q000096:biosynthesis; D006801:Humans; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000628:therapy*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors
D000069594:Abatacept; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D000939:Epitopes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015789:HLA-A2 Antigen; D018796:Immunoconjugates; D007371:Interferon-gamma; D018664:Interleukin-12; D010446:Peptide Fragments; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; C556706:CTLA4 protein, human; C474513:HER-2 peptide E75 (369-377), human