TY - JOUR
T1 - Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions
T2 - Lesion Clearance Is Related to the Strength of the T-Cell Response
AU - van Poelgeest, Mariëtte I E
AU - Welters, Marij J P
AU - Vermeij, Renee
AU - Stynenbosch, Linda F M
AU - Loof, Nikki M
AU - Berends-van der Meer, Dorien M A
AU - Löwik, Margriet J G
AU - Hamming, Ineke L E
AU - van Esch, Edith M G
AU - Hellebrekers, Bart W J
AU - van Beurden, Marc
AU - Schreuder, Henk W
AU - Kagie, Marjolein J
AU - Trimbos, J Baptist M Z
AU - Fathers, Lorraine M
AU - Daemen, Toos
AU - Hollema, Harry
AU - Valentijn, A Rob P M
AU - Oostendorp, Jaap
AU - Oude Elberink, J Hanneke N G
AU - Fleuren, Gertjan J
AU - Bosse, Tjalling
AU - Kenter, Gemma G
AU - Stijnen, Theo
AU - Nijman, Hans W
AU - Melief, Cornelis J M
AU - van der Burg, Sjoerd H
N1 - ©2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - PURPOSE: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101).EXPERIMENTAL DESIGN: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses.RESULTS: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance.CONCLUSIONS: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN.
AB - PURPOSE: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101).EXPERIMENTAL DESIGN: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses.RESULTS: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance.CONCLUSIONS: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN.
U2 - 10.1158/1078-0432.CCR-15-2594
DO - 10.1158/1078-0432.CCR-15-2594
M3 - Article
C2 - 26813357
SN - 1078-0432
VL - 22
SP - 2342
EP - 2350
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -