TLR2 ligand-synthetic long peptide conjugates effectively stimulate tumor-draining lymph node T cells of cervical cancer patients
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Gijs G. Zom1, Marij J.P. Welters2, Nikki M. Loof2, Renske Goedemans2, Sinéad Lougheed3, Rob R.P.M. Valentijn4, Maarten L. Zandvliet4, Nico J. Meeuwenoord5, Cornelis J.M. Melief1,6, Tanja D. de Gruijl3, Gijsbert A. Van der Marel5, Dmitri V. Filippov5, Ferry Ossendorp1,*, Sjoerd H. Van der Burg2,*
1Department of Immunohematology and Blood Transfusion, Section Tumorimmunology, Leiden University Medical Center, Leiden, The Netherlands
2Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
3Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
4Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
5Leiden Institute of Chemistry, University of Leiden, Leiden, The Netherlands
6ISA Pharmaceuticals BV, Leiden, The Netherlands
*These authors have contributed equally to this work
Ferry Ossendorp, email: [email protected]
Sjoerd H. Van der Burg, email: [email protected]
Keywords: Toll-like receptor ligand, conjugate, synthetic long peptide, cancer vaccine, cervical cancer
Received: April 19, 2016 Accepted: July 10, 2016 Published: August 23, 2016
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.
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