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

Schiza, AglaiaUppsala universitet,Experimentell och klinisk onkologi,Uppsala Univ Hosp, Dept Oncol, Entrance 78, S-75185 Uppsala, Sweden (författare)

Background and aims: Malignant 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). Methods: Peripheral 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. Results: All 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. Conclusions: AdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted.

Wenthe, JessicaUppsala universitet,Klinisk immunologi(Swepub:uu)jeswe849 (författare)
Mangsbo, Sara,1981-Uppsala universitet,Klinisk immunologi(Swepub:uu)saman132 (författare)
Svensson, EmmaUppsala universitet,Klinisk immunologi(Swepub:uu)emmsv898 (författare)
Nilsson, AndersUppsala Univ Hosp, Div Radiol, Uppsala, Sweden (författare)
Tötterman, ThomasUppsala universitet,Klinisk immunologi(Swepub:uu)thomtott (författare)
Loskog, Angelica,1973-Uppsala universitet,Klinisk immunologi(Swepub:uu)angelosk (författare)
Ullenhag, GustavUppsala universitet,Experimentell och klinisk onkologi,Uppsala Univ Hosp, Dept Oncol, Entrance 78, S-75185 Uppsala, Sweden(Swepub:uu)gustulle (författare)
Uppsala universitetExperimentell och klinisk onkologi (creator_code:org_t)

Ingår i:Journal of Translational Medicine: Springer Science and Business Media LLC15:791479-5876

Av författaren/redakt...: Schiza, Aglaia; Wenthe, Jessica; Mangsbo, Sara, 1 ...; Svensson, Emma; Nilsson, Anders; Tötterman, Thoma ...; visa fler...; Loskog, Angelica ...; Ullenhag, Gustav; visa färre...

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