Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients

Journal of Translational Medicine

Research

S. Mangsbo¹  T. H. Tötterman¹  A. Loskog¹  E. Eriksson¹  J. Wenthe¹  A. Schiza²  G. Ullenhag²  Anders Nilsson³ 

[1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden;Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden;Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85, Uppsala, Sweden;Division of Radiology, Uppsala University Hospital, Uppsala, Sweden;

关键词: AdCD40L;    Malignant melanoma;    Immunotherapy;    Proteomics;    T regulatory cells;    Myeloid-derived suppressor cells;   

DOI  :  10.1186/s12967-017-1182-z

 received in 2017-02-16, accepted in 2017-04-14,  发布年份 2017

来源: Springer

【 摘 要 】

Background and aimsMalignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L).MethodsPeripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics.ResultsAll patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival.ConclusionsAdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted.Trial registration The 002:CD40L trial “Phase I/IIa AdCD40L Immunogene Therapy for Malignant Melanoma and Other Solid Tumors” (clinicalTrials.gov identifier: NCT01455259) was registered at September 2011

【 授权许可】

CC BY   
© The Author(s) 2017