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


CONCLUSIONS
The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.
Academic Unit of Obstetrics and Gynaecology, University of Manchester, St Mary's Hospital, Whitworth Park, Manchester M13 0JH, UK.
S
S
Daayana
E
E
Elkord
U
U
Winters
M
M
Pawlita
R
R
Roden
P L
PL
Stern
H C
HC
Kitchener
D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000627:therapeutic use*; D000956:Antigens, Viral / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use; D002278:Carcinoma in Situ / Q000188:drug therapy*; D004361:Drug Tolerance; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D008875:Middle Aged; D053918:Papillomavirus Vaccines / Q000627:therapeutic use*; D014846:Vulvar Neoplasms / Q000188:drug therapy*; D055815:Young Adult
D000634:Aminoquinolines; D000956:Antigens, Viral; D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D000077271:Imiquimod