(UroToday.com) The 2026 AUA annual meeting featured a non-invasive bladder cancer session and a presentation by Dr. Michael Oefelein discussing Paradigm 1, a multicenter phase 1 study evaluating the safety and clinical effect of a novel microbial immunotherapeutic (ZH9) in patients with relapsed non-muscle invasive bladder cancer.
ZH9 is live attenuated Salmonella enterica serovar Typhi bacteria designed to induce a host anti-tumor immune response via upstream innate immune activation through multiple pattern recognition receptors, including toll-like receptors recognizing lipopolysaccharide, flagellin, and unmethylated cytosine-guanine dinucleotide motifs abundant in ZH9.
This mechanism of action results in enhanced local immune surveillance and antitumor immune memory, preventing recurrence. Non-clinical studies confirmed that ZH9 induces quantitatively and qualitatively superior immune cell infiltrates with different kinetics compared to BCG. Tailoring ZH9 intravesical instillation treatment dose and frequency (repeat dosing) to the patient’s individual clinical and immune response could extend the disease-free interval and improve quality of life in patients with non-muscle invasive bladder cancer, while reducing the overall number of intravesical instillations compared with the current standard of care.
This ongoing phase 1 study evaluates safety, tolerability, progressive disease, immunogenicity, and preliminary efficacy of ZH9 intravesical instillation in patients with relapsed non-muscle invasive bladder cancer (intermediate risk or high risk), with BCG status either “unresponsive” or “naïve”. The study will also determine the recommended phase 2 dose and schedule to inform further clinical studies and support the selection of the target patient population. The adaptive design allows for rapid dose escalation to active dose level(s), seamless expansion of cohorts, early evaluation of pharmacology, clinical effect, and repeat dosing. The primary endpoints are treatment-emergent adverse events, dose-limiting toxicities, and changes in clinical laboratory values. The main secondary endpoints include freedom from relapse at 3, 6, and 12 months, respectively, and exploratory endpoints include immunogenic and progressive disease markers, and quality of life.
There were 22 participants enrolled between January 2024 and June 2025, including 17 males and 5 females, with a median age of 70 (range: 47-89) years. The majority of patients were high risk (77%), and Ta tumor type (60%), with a median of 5 (range: 2-14) prior TURBTs, and 7/22 patients were BCG naïve.
There were 12 participants dosed in 4 cohorts with intravesical instillation doses from 1x108 CFU to 1x 1011 CFU. 10 participants were enrolled in the ongoing expansion cohort at 1x 1011 CFU. In terms of safety, a total of 13 treatment-emergent adverse events (mild dysuria, bladder spasm) occurred, and there were no symptomatic adverse events or dose-limiting toxicities. All events were transient and did not require changes in treatment.
Interim data of 11 patients who have completed the study notes that 91% had freedom from relapse at 12 months, which is encouraging given the heavily pre-treated population.
Finally, ZH9 triggers a local pro-inflammatory Th1 immune response with no systemic involvement, and a transient urinary immune response returns to baseline by week 12, supporting quarterly dosing.
Dr. Oefelein concluded his presentation discussing Paradigm 1 with the following take-home points:
- ZH9 is a next-generation intravesical live attenuated microbial immunotherapy
- ZH9 intravesical instillations are well tolerated as a single dose and quarterly maintenance, with a favorable safety profile
- There is promising activity with durable freedom from recurrence in the majority of patients
Presented by: Michael Oefelein, MD, FACS, Bakersfield Institute of Advanced Urology, Bakersfield, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Urological Association (AUA) 2026 Annual Meeting, Washington, DC, Fri, May 15 – Mon, May 18, 2026.