Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.

BACKGROUND: Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. METHODS: Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. RESULTS: As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. CONCLUSIONS: Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.

Intravesical Ty21a Treatment of Non-muscle-invasive Bladder Cancer Shows a Good Safety Profile.

Standard-of-care immunotherapy for non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmettte-Guérin (BCG) is associated with adverse events (AEs), disease recurrence/progression, and supply shortages. Preclinical data have shown that intravesical instillation of Ty21a/Vivotif, the oral vaccine against typhoid fever, may be an effective and safer alternative to BCG. We assessed the safety of intravesical Ty21a in NMIBC. For ethical reasons, patients with low- or intermediate-risk NMIBC not requiring BCG immunotherapy were enrolled. To determine the maximum tolerated dose, escalating doses of Ty21a/Vivotif were intravesically instilled in three patients once a week for 4 wk in phase 1a. In phase 1b, ten patients received the selected dose (1 × 108 CFU) once a week for 6 wk, as for standard BCG therapy. At this dose, all patients completed their treatment. Most patients experienced minor systemic AEs, while half reported mild local bladder AEs. AEs only occurred after one or two instillations for 40% of the patients. Ty21a bacteria were only recovered in three out of 72 urinary samples at 1 wk after instillation. Intravesical Ty21a might be well tolerated with no cumulative side effects, no fever >39 °C, and lower risk of bacterial persistence than with BCG. Ty21a treatment thus warrants clinical trials to explore its safety and antitumor efficacy in high-risk NMIBC. This trial is registered on ClinicalTrials.gov as NCT03421236. Patient summary: We examined the safety of a new intra-bladder immunotherapy for non-muscle-invasive bladder cancer as an alternative to the standard BCG treatment. Our data show that the Ty21a vaccine might be well tolerated. Further studies are needed to determine the safety and antitumor efficacy of this treatment.