Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538393
Title: Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia
Author: Daayana, Sai Lakshmi
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2011
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Abstract:
Vulval intraepithelial neoplasia (VIN) is a distressing, premalignant condition, frequently associated with type HPV16 infection, with increasing incidence in younger women. Traditional surgical treatment is sub optimal. Several different clinical studies influencing local and/or systemic immunity to HPV have been reported. Imiquimod, an immune response modifier, can stimulate local innate immunity and also drive an adaptive immune response. Therapeutic HPV vaccines are designed to generate cell-mediated immunity against HPV infected cells. The rationale of this study was that local imiquimod treatment, in addition to having a direct effect on VIN could also provide an immunological platform for the therapeutic HPV vaccination to achieve an enhanced and durable response. In this phase II trial, we used a combination of imiquimod and vaccination with TA-CIN (HPV16 E6E7L2 fusion protein). Women with biopsy proven high-grade VIN were recruited. Imiquimod treatment for 8 weeks was followed by three i.m. injections of TA-CIN. The objectives were to measure lesion size, histology, lesion HPV status, symptoms, immune responses before and after treatment as well as safety, toxicity, and tolerability. Lymphoproliferation to HPV antigens was used to analyse immunity to HPV before and after treatment. Local immune factors (CD4, CD8 and T regulatory cells) were assessed by immunofluorescence. 74, 85 and 79% of women had a ≥50% reduction in the size of lesion and 32, 58 and 63% had regression of VIN on histology at weeks 10, 20 and 52 respectively. At baseline, 79% had moderate to severe symptoms compared to 21% at week 52(P=0.01). Of the women who showed histological responses at week 52, 5/10 also cleared their HPV 16 infection. Follow-up for an average of 15 months showed 84% of patients with a ≥50% reduction in lesion size. Treatment was well tolerated. A significant post vaccination increase in proliferation to TA-CIN and its components was associated with histological responders (P=0.008) but not the non-responders (P=0.7). In the group as a whole, significant increases in the number of CD4, CD8 and T regulatory cells (Treg) were evident by week 20 compared to baseline (P=0.03, P=0.01, P= 0.04 respectively); At week 20, the increased CD4 and CD8 density was significantly associated only with the histological responders (P=0.03; P= 0.03) while increased Treg density was associated with only non-responders (P=0.05). Intralesional Treg density was significantly higher in non-responders compared to responders pre and post treatment (P=0.01, 0.05 respectively). This study demonstrated that imiquimod followed by vaccination achieved histological clearance of VIN at 52 weeks in almost 60%. Higher pre-existing and post-treatment levels of Treg cells were associated with a lack of treatment response. Lymphoproliferation of PBMC established that the vaccination was immunogenic and HPV 16 antigen specific. Importantly, these systemic immune responses to HPV 16 antigens were significantly associated with treatment responders.
Supervisor: Not available Sponsor: Professor H C Kitchener
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.538393  DOI: Not available
Keywords: vulval intraepithelial neoplasia, imiquimod, therapeutic HPV vaccination, T regulatory cells
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