Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives

The macrophage – a novel system to deliver gene therapy to pathological hypoxia

“…22 These studies and our data therefore allow us to envisage an improved therapeutic strategy for the treatment of cancer whereby the patient's macrophages are engineered ex vivo with a hypoxia-regulated gene for the expression of a prodrug activating enzyme and then returned to the tumour compartment. Following treatment of the patient with the prodrug, tumours would be selectively damaged by the macrophagemediated metabolism of the prodrug.…”

A novel magnetic approach to enhance the efficacy of cell-based gene therapies

“…5 However, to date, there has been little evidence to show that monocytes or macrophages manipulated ex vivo are capable of trafficking to the tumour site in sufficient numbers to elicit a therapeutic effect. 6,7 For example, macrophages stimulated with cytokines to be cytotoxic towards tumour cells in vitro largely became trapped in the fenestrated capillaries of the liver, lungs and kidneys following re-infusion into tumour-bearing mice 6,8 or cancer patients. 7,9 This prompted us to develop a way to use ultra-small, biocompatible magnetic particles (otherwise known as magnetic nanoparticles (MNPs)) to enhance the overall uptake of genetically engineered cells like monocytes or macrophages by tumours following their systemic administration.…”

Genetically modified macrophages expressing hypoxia regulated cytochrome P450 and P450 reductase for the treatment of cancer

“…The treatment strategy would typically involve patients undergoing apheresis to collect autologous monocytes, maturation to macrophages in the presence of GM-CSF, 'arming' of these macrophages via transduction with the Ad-PR vector and re-administration directly into the peritoneal cavity followed by an intraperitoneal infusion of CPA. The principle of this ex vivo approach has been shown to be safe and well-tolerated in human cancer clinical trials where at least 3x10 9 patient-derived macrophages were activated with either (IFN-Á) or LPS prior to re-infusion (10,22). In these studies the macrophages remained in the peritoneal cavity for over 7 days and accumulated at tumour sites (10).…”

“…TAMs are also attracted to the tumour site by chemokines produced by the tumour cells where they promote angiogenesis leading to tumour growth and spread (5). Classically, interferon (IFN)-Á-and/or lipopolysaccharide (LPS)-activated M1 macrophages which are involved in type I reactions produce reactive oxygen and nitrogen intermediates that have been found to be cytotoxic to tumour cells in vitro (5,9,10). However, there is a lack of in vivo evidence to confirm this observation.…”