Mary Lynne Hedley

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA–encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 μg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P = .12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P = .007). ZYC101a activity was not restricted to HPV-16– or HPV-18–positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Purpose: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1–specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy. Experimental Design: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-dl-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 μg every other week for up to 12 doses. Results: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year. Conclusions: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.

Dynamics of Human Papillomavirus Infection between Biopsy and Excision of Cervical Intraepithelial Neoplasia: Results from the ZYC101a Protocol

BACKGROUND Little is known about the dynamics of human papillomavirus (HPV) during the follow-up of cervical intraepithelial neoplasia (CIN) 2/3 after biopsy. METHODS A total of 127 women with biopsy-confirmed CIN2/3 were enrolled in a phase 2 double-blinded, randomized, placebo-controlled clinical trial of ZYC101a. Colposcopic, cytologic, and HPV testing were performed over the course of 6 months, before a loop electrical surgical excision procedure was performed at study exit. RESULTS Of the women tested, 99% were found to be HPV positive at study entry, 50% were found to be HPV type 16 positive at study entry, 22% were found to be positive for multiple HPV types at study entry, and 37% were found to be positive for additional HPV types during follow-up. Of those with a histologic outcome of CIN1 at study exit, 78% were found to be positive for additional HPV types; in 39%, the original type was replaced with a new HPV type. Virus load at study entry did not predict outcome, but pre-study-exit virus load correlated with a histologic outcome of any CIN, and changes in virus load correlated with risk for an outcome of CIN2/3 at study exit. CONCLUSIONS The type and number of HPVs at study entry, detection of additional viral types, and virus load changes during follow-up influence histologic outcome at study exit. An outcome of CIN1 at study exit is most likely due to additional HPV infections, rather than morphologic reversion of CIN2/3 to CIN1. Knowledge of the dynamics of HPV infection during the biopsy-to-excision period is critical to understanding the natural history of HPV infection, its contribution to disease outcome, and interpretations of drug efficacy.