PURPOSE A non-surgical alternative for treating cervical intraepithelial neoplasia (CIN) 2/3 is an unmet need due to a risk of cervical incompetency. METHODS PepCan consists of four human papillomavirus (HPV) type 16 E6 peptides and a Candida skin testing reagent (adjuvant). In this randomized, double-blind Phase 2 study, women with biopsy-confirmed CIN2/3 were treated with PepCan or Candida at one to one ratio. Four intradermal injections were given every 3 weeks, with observation visits at 6 and 12 months post-vaccination. Quadrant biopsies were performed at the 12-month visit, and those whose lesions regressed to no CIN were considered to be complete responders. Regression rates of each treatment group were compared to that of a historical placebo group. RESULTS With the intention-to-treat analysis, PepCan (n=39) showed 30.8% efficacy (95% confidence interval [CI], 17 to 47.6; p=0.25) while Candida (n=42) demonstrated 47.6% efficacy (95% CI, 32 to 63.6; p<0.001). Likewise, with the per-protocol analysis, PepCan (n=24) showed 45.8% efficacy (95% CI, 25.6 to 67.2; p=0.08) and Candida (n=29) showed 62.1% efficacy (95% CI, 42.3 to 79.3; p<0.001). There was no difference between efficacy of PepCan and Candida. No dose-limiting toxicity was observed. HPV-specific T cell responses were elicited in both groups. Vaccine-induced HPV-specific CD4 and CD8 T cells were present in cervix regardless of histological response. Single-cell RNA-seq revealed increased expression of granzymes, CCR5, and EOMES in HPV-specific CD8-positive T cells of a histological responder, compared to non-responders. Six cytokines (CCL4, CCL5, interleukin-9, lymphotoxin-α, platelet-derived growth factor-ββ, tumor growth factor-β1) were significantly decreased in both Candidarecipients and histological responders suggesting that Candida may possibly exert its anti-tumor effects through these systemic mediators. CONCLUSIONS Candida may be effective in inducing histological regression. PepCan and Candida treatments are safe. Candida should be evaluated in a Phase 3 trial as a potential new treatment for CIN2/3.

Mayumi Nakagawa is one of the inventors named in patents and patent applications for PepCan and Candida. Other authors declare no potential conflicts of interest.

NCT02481414

This study was supported by grants from the National Institutes of Health (R01CA143130 and UL1 TR003107).

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