1173P - Immunostimulatory AdCD40L gene therapy in patients with advanced solid tumours

Abstract

Background: CD40-CD40L is a key activator of adaptive immunity. AdCD40L is a replication-deficient adenovirus carrying the CD40 ligand gene. We have conducted a phase I/II study (NCT01455259) for patients with advanced cancer receiving intratumoral injections of AdCD40L. Patients with metastatic malignant melanoma were treated in the first three cohorts in which we demonstrated that low dose cyclophosphamide before the first and fourth intratumoral injection given in the second and the third cohort was of clinical value with four patients surviving >1 year, while radiotherapy combination was not. In these patients, AdCD40L increased the Teffector to Tregulatory cell ratio showing its action via T cell activation. We now report the results of the fourth and final cohort treating patients with other solid malignancies. Methods: Six patients with metastatic solid cancer underwent treatment with four weekly percutaneous intratumoral injections of 2.5x1011 VP AdCD40L and low dose cyclophosphamide conditioning (300 mg/m2) before the first and fourth injection. All patients had good performance status at inclusion. The primary tumor was kidney cancer (n = 2) or cholangiocarcinoma (n = 1), rectal- (n = 1), ovarian- (n = 1), and breast cancer (n = 1). Correlation analysis between immunological data and survival was performed. Results: The treatment was generally well tolerated. Patients received the injection in metastases located in the liver (n = 4), lymph node (n = 1), or muscle (n = 1). The performance status for one patient improved during the treatment and this patient was therefore accepted for re-treatment. The median survival was 54 weeks ranging from 5 to 101 weeks compared to the melanoma patients that had a median survival of 27 weeks (5 to 220 weeks). Immunological data from five of the patients showed a significant negative correlation between IL10 concentrations at week 3 and survival (p = 0.0283). In addition, TNFα and IL12 was higher post-treatment in the two patients with the longest survival. Conclusions: Intratumoral injections of AdCD40L in combination with cyclophosphamide is feasible in patients with solid cancer. Desirable immune effects were noted and the potential of the treatment was also demonstrated in one patient who improved clinically. Clinical trial identification: NCT01455259 Realease date: September 2011. Legal entity responsible for the study: Landstinget Region Uppsala. Funding: Supported by grants to Dr Ullenhag by the research foundation Stiftelsen Onkologiska Kliniken i Uppsala Forskningsfond and Lions’s Cancer Fund at Uppsala University Hospital and by grants to Dr Tötterman and Dr Loskog from the Swedish Cancer Society, Medical Faculty at Uppsala University and the Swedish State Support for Clinical Research and Lion’s Cancer Fund at Uppsala University Hospital. Disclosure: H. Ahlström: Founder and employee: Antaros Medical AB. T. Tötterman: Royalty agreement: Alligator Bioscience AB; Board member and shareholder: Immuneed AB. Advisor of Alligator Bioscience AB. A. Loskog: CEO, board member, royalty agreement and research grant: Lokon Pharma AB; Advisor: Nexttobe AB; Chairman of the board: Vivolux AB; Chairman of the board: Repos Pharma AB; Board member: Hansa Medical AB; Board member: Bioimics AB; Royalty agreement: Alligator Bioscience AB. G. Ullenhag: Medical advisor: Lokon Pharma AB. All other authors have declared no conflicts of interest.