Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients

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.

Evaluation of Diffusion-Weighted MRI and FDG-PET/CT to Assess Response to AdCD40L treatment in Metastatic Melanoma Patients

“…The phase I/IIa study (NCT01455259, registration date 19/10/2011; Sponsor’s Protocol Code Number, 002:CD40L) was conducted in compliance with our protocol (EudraCT 2010-023103-94, date of registration 26/09/2010), in accordance with the international conference of harmonization – good clinical practice guidelines, the principles of the Declaration of Helsinki and applicable regulatory guidelines, and was approved by the Regional Ethical Review Board in Uppsala and the Medical Products Agency. The patient characteristics, feasibility, safety and efficacy of the AdCD40L-treatment have been published previously 36,37 . Briefly, 24 patients (mean age 62.5 years, 23–79 years) with refractory disseminated, histologically proven, MM with ≥ 2 measurable lesions according to the RECIST 1.1, were enrolled October 2011-January 2015.…”

“…All the patients received all established treatments. One third of the patients received some type of immunotherapy prior to study enrollment 37 . All other therapies were, however, stopped due to PD before the 10-week DWI- and PET- monitoring period.…”

“…All patients (n = 24) have been previously reported 36,37 . These two prior reports comprised the radiological evaluation of the study subjects by FDG-PET/CT and WB-MRI according to RECIST 1.1 as well as by FDG-PET in the injected metastases according to EORTC criteria.…”

Concepts for agonistic targeting of CD40 in immuno-oncology

“…Additional developments in both the delivery method and the format of CD40L have also shown promise. 30,56,[61][62][63]…”