Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients

Small scale phase I/IIa clinical trial for use of an adenoviral expression vector for CD40 ligand (AdCD40L) to treat patients with advanced metastatic malignant melanoma (MM). Current treatments are ineffective and very toxic – intention here is to stimulate CD40+ immune cells to attack the tumor cells. Patients given multiple injections of AdCD40L, with or without pre-treatment with an immune system activating drug (cyclophosphamide). No “objective response” was seen (e.g. no reduction of tumor load), but some local and distant improvements in reduced tumor cell metabolism were observed. 6 month survival was better in subjects who had cyclophosphamide. Patients with the best survival times showed highest levels of activated T-cells. Proseek data was used to provide pathophysiological input to supplement the clinical observations. Looked for IFN-gamma (previously seen as an effector marker for AdCD40L treatment of bladder cancer) but this was undectable in the MM patients. Suspected this was due to intensive pre-treatment of these patients prior to the trial and interestingly, did find expression of the INF-gamma activated proteins CXCL 9 & 10. Also saw increased levels of caspase 8 after treatment, which is a possible marker of AdCD40L-induced tumor cell death. Two patients showed a pronounced reduction of IL8 (pro-angiogenic and metastasis factor) in their tumor tissue following treatment and there was some overall correlation seen between reduction in IL8 level pre/post therapy and overall survival time. Only 1/15 patients in the trial survived beyond 3 years, but the mild clinical benefits seen in some subjects together with reduced toxicity compared to current treatments were assessed as being encouraging.