Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

• Published in: British journal of cancer Vol. 102; no. 7; pp. 1129 - 1136
• Main Authors: Daayana, S, Elkord, E, Winters, U, Pawlita, M, Roden, R, Stern, P L, Kitchener, H C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-03-2010; Nature Publishing Group
• Subjects: 631/154/109/1941; 692/699/255/2514; 692/699/67/1517; 692/700/565/251/1567; Adolescent; Adult; Aged; Aminoquinolines - therapeutic use; Antigens, Viral - analysis; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer Vaccines - therapeutic use; Carcinoma in Situ - drug therapy; Drug Resistance; Drug Tolerance; Epidemiology; Female; Human papillomavirus; Human papillomavirus 16; Human papillomavirus 16 - immunology; Humans; Medical sciences; Middle Aged; Molecular Medicine; Oncology; Papillomavirus Vaccines - therapeutic use; Translational Therapeutics; Tumors; Vulvar Neoplasms - drug therapy; Young Adult; therapeutic HPV vaccination; T regulatory cells; vulval intraepithelial neoplasia (VIN); imiquimod; Human; Imiquimod; Vaccination; vulval intraepithelial neoplasia (VIN): imiquimod; Papovaviridae; Papillomavirus; Virus; Prevention; Human papillomavirus; Cancerology; Treatment; Phase II trial; T-Lymphocyte; Intraepithelial neoplasia; Regulatory cell
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605611

Background:
Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure.
Methods:
We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed.
Results:
Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, non-responders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens.
Conclusion:
The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.