Oncotarget

Research Papers:

TLR2 ligand-synthetic long peptide conjugates effectively stimulate tumor-draining lymph node T cells of cervical cancer patients

Gijs G. Zom _, Marij J.P. Welters, Nikki M. Loof, Renske Goedemans, Sinéad Lougheed, Rob R.P.M. Valentijn, Maarten L. Zandvliet, Nico J. Meeuwenoord, Cornelis J.M. Melief, Tanja D. de Gruijl, Gijsbert A. Van der Marel, Dmitri V. Filippov, Ferry Ossendorp, Sjoerd H. Van der Burg

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Oncotarget. 2016; 7:67087-67100. https://doi.org/10.18632/oncotarget.11512

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Abstract

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

Correspondence to:

Ferry Ossendorp, email: f.a.ossendorp@lumc.nl

Sjoerd H. Van der Burg, email: shvdburg@lumc.nl

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

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.


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