Effect of Montanide and poly-ICLC adjuvant on human self/tumor antigen-specific CD4+ T cells in phase I overlapping long peptide vaccine trial.
Vaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4(+), and CD8(+) T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1-specific CD4(+) T cells, because of their central function for induction and maintenance of both antibody and CD8(+) T cells. Polyclonal NY-ESO-1-specific CD4(+) T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4(+) T-cell responses; it suppressed high-avidity CD4(+) T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1-specific CD4(+) T-cell precursors. Poly-ICLC significantly enhanced CD4(+) Th1 responses while suppressing the induction of interleukin (IL)-4-producing Th2 and IL-9-producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1-specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines.
Authors' Affiliations: Oncovir, Washington, District of Columbia.
Takemasa
T
Tsuji
Paul
P
Sabbatini
Achim A
AA
Jungbluth
Erika
E
Ritter
Linda
L
Pan
Gerd
G
Ritter
Luis
L
Ferran
David
D
Spriggs
Andres M
AM
Salazar
Sacha
S
Gnjatic
D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D008353:Mannitol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D009829:Oleic Acids / Q000008:administration & dosage* / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage* / Q000276:immunology; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; D009829:Oleic Acids; D010455:Peptides; C477385:montanide ISA 51; D023201:CD40 Ligand; D011107:Polylysine; D008353:Mannitol; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C