title: Rapid and Continued T-Cell Differentiation into Long-term Effector and Memory Stem Cells in Vaccinated Melanoma Patients.
abstract: Purpose:Patients with cancer benefit increasingly from T-cell-based therapies, such as adoptive T-cell transfer, checkpoint blockade, or vaccination. We have previously shown that serial vaccinations with Melan-AMART-126-35peptide, CpG-B, and incomplete Freund adjuvant (IFA) generated robust tumor-specific CD8 T-cell responses in patients with melanoma. Here, we describe the detailed kinetics of early- and long-term establishment of T-cell frequency, differentiation (into memory and effector cells), polyfunctionality, and clonotype repertoire induced by vaccination.Experimental Design:Twenty-nine patients with melanoma were treated with multiple monthly subcutaneous vaccinations consisting of CpG-B, and either the native/EAA (n= 13) or the analogue/ELA (n= 16) Melan-AMART-126-35peptide emulsified in IFA. Phenotypes and functionality of circulating Melan-A-specific CD8 T cells were assessed directlyex vivoby multiparameter flow cytometry, and TCR clonotypes were determinedex vivoby mRNA transcript analyses of individually sorted cells.Results:Our results highlight the determining impact of the initial vaccine injections on the rapid and strong induction of differentiated effector T cells in both patient cohorts. Moreover, long-term polyfunctional effector T-cell responses were associated with expansion of stem cell-like memory T cells over time along vaccination. Dominant TCR clonotypes emerged early and persisted throughout the entire period of observation. Interestingly, one highly dominant clonotype was found shared between memory and effector subsets.Conclusions:Peptide/CpG-B/IFA vaccination induced powerful long-term T-cell responses with robust effector cells and stem cell-like memory cells. These results support the further development of CpG-B-based cancer vaccines, either alone or as specific component of combination therapies.Clin Cancer Res; 23(13); 3285-96. ©2016 AACR.
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.
authors.forename: Philippe O
authors.initials: PO
authors.lastname: Gannon
authors.affiliation: Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Huber
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Iancu
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.|Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Laurène
authors.initials: L
authors.lastname: Cagnon
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.|Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Samia
authors.initials: S
authors.lastname: Abed Maillard
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland.|Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Maby-El Hajjami
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland. Nathalie.Rufer@unil.ch doc@dspeiser.ch.|Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland. Nathalie.Rufer@unil.ch doc@dspeiser.ch.|Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
mesh_terms: D019264:Adoptive Transfer; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D005620:Freund's Adjuvant / Q000276:immunology / Q000627:therapeutic use; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D008055:Lipids / Q000276:immunology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D058965:MART-1 Antigen / Q000276:immunology* / Q000627:therapeutic use; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D008055:Lipids; D058965:MART-1 Antigen; C548667:MLANA protein, human; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant