A heterologous prime-boost strategy using RUTI vaccine to improve the BCG response in non–muscle-invasive bladder cancer patients (RUTIVAC-1 trial).

801 Background: Despite standard-of-care therapy with transurethral resection of bladder tumor and intravesical BCG instillation, a significant percentage of patients with non-muscle invasive bladder cancer (NMIBC) experience disease recurrence or progression. Therefore, novel combination therapies are needed to improve BCG efficacy. The RUTIVAC-1 trial, a randomized, double-blind, placebo-controlled, phase I study, was conducted to investigate the potential of a heterologous prime-boost strategy using RUTI, a nonlive vaccine composed of Mycobacterium tuberculosis cell wall fragments, as a primer to enhance the intravesical BCG-induced immune response in NMIBC patients. Methods: Forty high-grade, BCG-naïve NMIBC patients were randomized 1:1 to receive two subcutaneous doses of either placebo or RUTI (25 μg) before standard BCG treatment. The primary endpoint was the immunological changes after RUTI vaccination. Secondary endpoints included clinical efficacy (recurrence, progression and mortality rates) and safety at 5-year follow-up. Results: Baseline characteristics were similar in both groups (median age 70 years, 90% male, 65% T1, 32.5% Ta and 4% CIS). RUTI vaccination induced a vaccine-specific CD4 + and CD8 + T cell response prior to the initiation of intravesical BCG therapy. Following intravesical BCG treatment, the placebo group showed an increase in regulatory T cells (Tregs; CD4 + CD25 + CD27 + ), which was not observed in the RUTI group. Conversely, RUTI-vaccinated patients exhibited a more heterogeneous and polyfunctional specific immune response, with significant increases in PPD-specific CD25 + , CD137 + , OX40 + and CD69 + CD4 + T cells, as well as bi- and trifunctional CD4 + T cells expressing IFN-γ, TNF-α, and IL-2. Efficacy after 5 years of follow-up correlated with immunological changes, with RUTI vaccination associated with a significant increase in progression-free survival (100% vs. 72.2%; p=0.015), an 80% reduction in the risk of experiencing an event (EFS 89.5% vs. 50%; HR: 0.2, 95% CI 0.06–0.69; p=0.024) and a higher cancer-specific disease-free survival rate (100% vs. 83.3%; p=0.067). RUTI was safe, with only low-grade injection site reactions and no systemic effects. Conclusions: RUTI vaccination prior to intravesical BCG treatment in NMIBC patients is safe and effectively modulates the BCG-induced immune response, promoting a more balanced effective/suppressive response. This novel approach has the potential to significantly improve clinical outcomes in the management of NMIBC. Clinical trial information: NCT03191578 .