Abstract
BackgroundAdCD40L 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.MethodsAdCD40L 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.ResultsAdCD40L 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.ConclusionsAdCD40L 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.
Highlights
The incidence of malignant melanoma (MM) has steadily increased in the past decades [1]
AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy
Recent treatment advances with BRAF and MEK inhibitors and the checkpoint blockade antibodies targeting CTLA4, PD1 or PDL1 have led to improved survival
Summary
The incidence of malignant melanoma (MM) has steadily increased in the past decades [1]. Recent treatment advances with BRAF and MEK inhibitors and the checkpoint blockade antibodies targeting CTLA4, PD1 or PDL1 have led to improved survival. BRAF and MEK inhibitors are only indicated in treatment of patients with BRAF V600 mutated tumors and they and all other available treatments are associated with severe side effects. Data is limited, pooled analyses and smaller studies have indicated that checkpoint blockade antibodies are less effective in patients with mucosal MM [3] and there is www.impactjournals.com/oncotarget even less evidence of efficacy in patients with uveal MM [4, 5]. Patients that do not respond to checkpoint blockade therapy may have few tumor infiltrating T cells, which is a prerequisite to respond. Defining other immunotherapeutic options that activate and expand tumor-infiltrating T cells such as local immunostimulatory gene therapy may be of interest. We present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy
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