Enhanced antitumoral effect of adenovirus-mediated cytosine deaminase genetherapy by induction of antigen-presenting cells through stem cell factor/granulocyte-macrophage colony-stimulating factor gene transfer

Suicide gene therapy has been studied intensively for the treatment of canc er. A limited antitumoral effect was obtained by intratumoral injection of adenovirus harboring Escherichia coli cytosine deaminase gene (AdCD) in tum or-bearing mice followed by continuous administration of 5-fluorocytosine ( 5FC). To address the drawbacks of the limited potential for the induction o f antitumoral immunity by CD suicide gene therapy, we hypothesized that ant igen-presenting cells (APCs) might contribute to the efficient induction of an antitumoral immune response in tumor-bearing mice undergoing suicide ge ne therapy. We preinjected the mice with murine stem cell factor (SCF)-enco ding adenovirus (AdSCF) and murine granulocyte-macrophage colony-stimulatin g factor (CM-CSF)-encoding adenovirus (AdGM-CSF); after 7 days, the mice we re inoculated with CT26 colon adenocarcinoma. AdCD was injected intratumora lly into tumor-bearing mice followed by 5FC administration. The results sho wed that AdSCF/AdGM-CSF treatment could increase the number, surface molecu le expression, and function of APCs efficiently. A more significant growth inhibition of established tumors and a prolongation of the survival period were observed in tumor-bearing mice after AdSCF/AdGM-CSF pretreatment in co mbination with AdCD/5FC therapy when compared with mice treated with AdSCF or AdGM-CSF in combination with AdCD/5FC, or AdCD/5FC alone (P < .01). Cyto toxic T-lymphocyte activity was induced efficiently after the combined ther apy, and mRNA of tumor necrosis factor-alpha, interleukin-4, interferon-gam ma, and interleukin-2 was present in the tumor mass after combined therapy, suggesting that a more potent antitumoral response was induced by enhanced APCs. Our results demonstrated that AdSCF/AdGM-CSF pretreatment could acti vate APCs, and that these APCs could present the tumor antigens released fr om AdCD/5FC-killed tumor cells and activate the antitumoral response of the host, thus increasing the therapeutic efficiency of suicide gene therapy.