Phase I/IIclinical trial of local GM-CSF application in patients with cervical HPV-associated low grade squamous intraepithelial lesions

Background: Quantitative and functional alterations of professional antigen-presenting cells (APC) in SIL suggest that these lesions may have a diminished capacity to capture viral antigens. Moreover, GM-CSF (whose production is decreased in HPV-transformed keratinocytes) is an essential factor for the migration of APC in cervical (pre)neoplastic lesions formed in vitro and transplanted in vivo on mouse. In this study we performed a phase I/II clinical trial in order to determine whether a local application of GM-CSF on cervical low-grade squamous intraepithelial lesions (LSIL) might increase the recruitment of APC into the epithelium and indirectly the viral antigen presentation to the immune system. Methods: Fifteen patients with LSIL (10 GM-CSF and 5 placebo) were enrolled in this study. Patients received 4 GM-CSF applications (or placebo gel) and were followed during 6-7 months. APC infiltration was quantified by immunostaining with anti-CD1a mAb. Cellular immune response was evaluated by using an IFN-gamma intracellular staining on PBMC stimulated in vitro with the E7 HPV16 protein and L1 HPV16 Virus-like particles (VLP). Hybrid capture was performed to semi-quantify the viral DNA in cervical brush specimens. Results: GM-CSF applications were well tolerated in all patients. No difference in the cytological/histological and viral parameters assessed at 2 and 6 months after the last application was observed between the GM-CSF and the placebo group. An increased number of CD1a+ APC was observed in 6/10 patients treated by GM-CSF compared to 1/5 patient in the placebo group. There was an increased immune response against HPV in the GM-CSF group showed by NK and T cells producing IFN-gamma