Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
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Sandra Irenaeus1,2, Aglaia Schiza1,2, Sara M. Mangsbo1, Jessica Wenthe1, Emma Eriksson1, Johan Krause3, Anders Sundin3,4, Håkan Ahlström3,4, Thomas H. Tötterman1, Angelica Loskog1 and Gustav J. Ullenhag1,2
1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
2Department of Oncology, Uppsala University Hospital, 751 85, Uppsala, Sweden
3Department of Radiology, Uppsala University Hospital, 751 85, Uppsala, Sweden
4Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden
Gustav J. Ullenhag, email: [email protected]
Keywords: malignant melanoma, AdCD40L, gene therapy, irradiation, immunotherapy
Received: April 11, 2017 Accepted: June 19, 2017 Published: July 31, 2017
Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy.
Methods: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival.
Results: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood.
Conclusions: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.
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