A Randomized Double-Blind Phase 2 Clinical Trial Treating Cervical Intraepithelial Neoplasia 2/3 with PepCan or Candida

PURPOSEA non-surgical alternative for treating cervical intraepithelial neoplasia (CIN) 2/3 is an unmet need due to a risk of cervical incompetency. METHODSPepCan 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. RESULTSWith 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-, platelet-derived growth factor-{beta}{beta}, tumor growth factor-{beta}1) were significantly decreased in both Candida recipients and histological responders suggesting that Candida may possibly exert its anti-tumor effects through these systemic mediators. CONCLUSIONSCandida 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.