Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909.
T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.
Department of Hematology, University Medical Center Utrecht, Lundlaan 6, Utrecht, The Netherlands. j.h.e.kuball@umcutrecht.nl
Jürgen
J
Kuball
Karin
K
de Boer
Eva
E
Wagner
Mohammed
M
Wattad
Edite
E
Antunes
Risini D
RD
Weeratna
Alain P
AP
Vicari
Carina
C
Lotz
Suzanne
S
van Dorp
Samantha
S
Hol
Philip D
PD
Greenberg
Wolfgang
W
Heit
Heather L
HL
Davis
Matthias
M
Theobald
D000293:Adolescent; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008353:Mannitol / Q000009:adverse effects / Q000031:analogs & derivatives*; D018396:Mucin-1 / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D053146:Myeloblastin / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009829:Oleic Acids / Q000009:adverse effects; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects / Q000276:immunology; D010455:Peptides / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D010865:Pilot Projects; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018396:Mucin-1; D009829:Oleic Acids; D009838:Oligodeoxyribonucleotides; D010455:Peptides; C483020:ProMune; D025721:WT1 Proteins; C477385:montanide ISA 51; D008353:Mannitol; D053146:Myeloblastin