• [CLINICAL CANCER RESEARCH] Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Pat
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[Title]
Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147)

[Author]

Sangini S. Sheth1, Ji Eun Oh2, Stefania Bellone3, Eric R. Siegel4, Michelle Greenman3, Levent Mutlu3, Blair McNamara3, Shefali Pathy1, Mitchell Clark3, Masoud Azodi3, Gary Altwerger3, Vaagn Andikyan3, Gloria Huang3, Elena Ratner3, Daniel J. Kim5,6, Akiko Iwasaki5,6, Angelique W. Levi7, Natalia Buza7, Pei Hui7, Sean Flaherty1, Peter E. Schwartz3, and Alessandro D. Santin3

1Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Specialties and Smilow Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
2Laboratory of Skin and Mucosal Immunology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of South Korea.
3Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Smilow Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
4Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
5Department of Immunobiology, Yale University, New Haven, Connecticut.
6Howard Hughes Medical Institute, Chevy Chase, Maryland.
7Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

S.S. Sheth and J.E. Oh contributed equally to this article.


[Journal] 

Clinical Cancer Research volume 30, Issue 9, 1 May 2024

[Abstract]

Purpose:

We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients.

Patients and Methods:

We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms.

Results:

Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated.

Conclusions:

Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

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