title: TLR2 ligand-synthetic long peptide conjugates effectively stimulate tumor-draining lymph node T cells of cervical cancer patients.
abstract: The potency of human papillomavirus type 16 (HPV16)-encoded synthetic long peptides (SLP), conjugated to an optimized Toll-like receptor 2 ligand (TLR2-L), was assessed in ex vivo activation of HPV16+ cancer patient-derived T cells. Two highly immunogenic SLP sequences derived from the oncogenic E6 protein of HPV16 were selected and conjugated to a Pam3CSK4-based TLR2-L under GMP conditions. Both conjugates were able to mature human DCs in vitro and to activate human skin-derived antigen-presenting cells (APCs) upon intradermal injection in an ex vivo skin model, associated with induction of a favorable chemokine profile to attract and activate T cells. The conjugated SLPs were efficiently processed by APCs, since HPV16-specific CD4+ and CD8+ T-cell clones isolated from HPV16+ cervical tumors proliferated in response to both conjugates. The TLR2-L SLP conjugates significantly enhanced ex vivo T helper type 1 T-cell activation in cell suspensions obtained from tumor-draining lymph nodes (LN) resected during hysterectomy of HPV16+ cervical cancer patients. These results show that TLR2-L SLP conjugates can activate circulating or LN-derived tumor-specific T cells, a promising outcome for studying these two conjugates in a phase I/II clinical safety and immunogenicity trial.
authors: Department of Immunohematology and Blood Transfusion, Section Tumorimmunology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Gijs G
authors: GG
authors: Zom
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Marij J P
authors: MJ
authors: Welters
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Nikki M
authors: NM
authors: Loof
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Renske
authors: R
authors: Goedemans
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Sinéad
authors: S
authors: Lougheed
authors: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rob R P M
authors: RR
authors: Valentijn
authors: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Maarten L
authors: ML
authors: Zandvliet
authors: Leiden Institute of Chemistry, University of Leiden, Leiden, The Netherlands.
authors: Nico J
authors: NJ
authors: Meeuwenoord
authors: Department of Immunohematology and Blood Transfusion, Section Tumorimmunology, Leiden University Medical Center, Leiden, The Netherlands.|ISA Pharmaceuticals BV, Leiden, The Netherlands.
authors: Cornelis J M
authors: CJ
authors: Melief
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Tanja D
authors: TD
authors: de Gruijl
authors: Leiden Institute of Chemistry, University of Leiden, Leiden, The Netherlands.
authors: Gijsbert A
authors: GA
authors: Van der Marel
authors: Leiden Institute of Chemistry, University of Leiden, Leiden, The Netherlands.
authors: Dmitri V
authors: DV
authors: Filippov
authors: Department of Immunohematology and Blood Transfusion, Section Tumorimmunology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Ferry
authors: F
authors: Ossendorp
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Sjoerd H
authors: SH
authors: Van der Burg
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D052162:Human papillomavirus 16; D006801:Humans; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D009856:Oncogene Proteins, Viral / Q000276:immunology* / Q000494:pharmacology; D012097:Repressor Proteins / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D008024:Ligands; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
keywords: Toll-like receptor ligand; cancer vaccine; cervical cancer; conjugate; synthetic long peptide