A Novel Heterologous Prime-boost Strategy Using RUTI Vaccine to Improve the Bacillus Calmette-Guérin Response in Non-muscle-invasive Bladder Cancer Patients: Phase 1 RUTIVAC-1 Trial

Intravesical bacillus Calmette-Guérin (BCG) is the standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC); however, recurrence and progression remain major challenges. To explore a heterologous prime-boost strategy, we conducted the RUTIVAC-1 trial (NCT03191578) to evaluate RUTI, a nonlive vaccine, derived from Mycobacterium tuberculosis, as a systemic primer prior to intravesical BCG in high-risk NMIBC patients. The immunogenicity, safety, and preliminary efficacy of RUTI was evaluated. In this phase 1, randomized, double-blind, placebo-controlled trial, 40 NMIBC patients were randomized 1:1 to receive two subcutaneous doses of RUTI (25 μg) or placebo before BCG treatment. Immunogenicity was assessed by flow cytometry, and clinical follow-up was extended to 5 yr. RUTI induced a systemic vaccine-specific response, increasing activation markers on CD4 + and CD8 + T cells, supporting effective immune priming. Regulatory T-cell expansion was observed in the placebo group but not in RUTI-vaccinated patients, who also exhibited a more heterogeneous and polyfunctional specific immune response. RUTI was safe and well tolerated, with only mild injection-site reactions. Exploratory analyses showed a trend toward reduced recurrence, progression, and death, with improved 5-yr progression-free survival. The small sample size and baseline imbalances were the limitations. This phase 1 study supports the safety and immunogenicity of RUTI and provides encouraging data that warrant confirmation in larger trials to establish its potential clinical benefit as a novel therapeutic strategy.