Simultaneous CD8+ T cell responses to multiple tumor antigen epitopes in a multipeptide melanoma vaccine.
The recent identification and molecular characterization of tumor-associated antigens recognized by tumor-reactive CD8+ T lymphocytes has led to the development of antigen-specific immunotherapy of cancer. Among other approaches, clinical studies have been initiated to assess the in vivo immunogenicity of tumor antigen-derived peptides in cancer patients. In this study, we have analyzed the CD8+ T cell response of an ocular melanoma patient to a vaccine composed of four different tumor antigen-derived peptides administered simultaneously in incomplete Freund's adjuvant (IFA). Peptide NY-ESO-1(157-165) was remarkably immunogenic and induced a CD8+ T cell response detectable ex vivo at an early time point of the vaccination protocol. A CD8+ T cell response to the peptide analog Melan-A(26-35 A27L) was also detectable ex vivo at a later time point, whereas CD8+ T cells specific for peptide tyrosinase(368-376) were detected only after in vitro peptide stimulation. No detectable CD8+ T cell response to peptide gp100(457-466) was observed. Vaccine-induced CD8+ T cell responses declined rapidly after the initial response but increased again after further peptide injections. In addition, tumor antigen-specific CD8+ T cells were isolated from a vaccine injection site biopsy sample. Importantly, vaccine-induced CD8+ T cells specifically lysed tumor cells expressing the corresponding antigen. Together, these data demonstrate that simultaneous immunization with multiple tumor antigen-derived peptides can result in the elicitation of multiepitope-directed CD8+ T cell responses that are reactive against antigen-expressing tumors and able to infiltrate antigen-containing peripheral sites.
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), 1011 Lausanne, Switzerland. valmori@cancercenter.columbia.edu
Danila
D
Valmori
Valérie
V
Dutoit
Maha
M
Ayyoub
Donata
D
Rimoldi
Philippe
P
Guillaume
Danielle
D
Liénard
Ferdy
F
Lejeune
Jean-Charles
JC
Cerottini
Pedro
P
Romero
Daniel E
DE
Speiser
D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004334:Drug Administration Schedule; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D015789:HLA-A2 Antigen / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D008055:Lipids / Q000008:administration & dosage / Q000276:immunology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000517:prevention & control; D008565:Membrane Proteins; D014442:Monophenol Monooxygenase / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011506:Proteins / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000276:immunology* / Q000517:prevention & control; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D008055:Lipids; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011506:Proteins; D022223:Vaccines, Subunit; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant; D014442:Monophenol Monooxygenase