Immunotherapy has been transformative for the treatment of cancer and has firmly established itself as a key therapeutic pillar. Unlike prior approaches, immunotherapy focuses on strategies to harness the patient’s immune system to detect and eradicate malignant cells. William Coley’s work, as long ago as the 1890’s, showing that bacterial infections could induce cancer regression was perhaps the first example of cancer immunotherapy. More than a century later, the bacterial therapy Bacillus Calmette–Guérin (BCG) is the mainstay treatment for non-muscle-invasive bladder cancer (NMIBC) and has been for almost 40 years. BCG provides compelling proof that live bacteria can be harnessed to stimulate the immune system against cancer. Following this precedent, we believe drug developers are set to bring a new generation of bacterial immunotherapies to fruition to deliver on the promise of Coley’s work, offering the potential for a new class of targeted, rationally designed treatments.

The challenge in NMIBC

Bladder cancer, of which NMIBC represents approx. 75-80% of cases, accounts for over 600,000 new diagnoses per year and over 220,000 deaths. It is the 6th most common cancer in men globally and 10th most common overall [1]. Whilst mortality is relatively low (>75% 5-year survival;[2]), it is a debilitating disease where treatment involves extensive monitoring, frequent clinician administered treatment and as a result, NMIBC has been reported to have the highest lifetime treatment cost of any cancer [3].

First-line treatment with BCG is effective, with decades of data showing positive outcomes, but it has substantial shortcomings for both patients and urologists. Treatment burden is incredibly high, with initial BCG induction therapy alone comprising 6 weekly intravesical (local delivery to the bladder through a catheter) doses and optimum maintenance extending the schedule up to 15-18 intravesical doses in the first year alone. This treatment burden, compounded by BCG’s side effect profile, can significantly impact patient compliance, with up to 50% of patients failing to complete a full year of maintenance therapy [4][5]. In addition, there is a global shortage of BCG related to its complicated manufacturing process, which is most acutely felt in the United States where there is only a single approved supplier.

Prokarium’s answer in NMIBC

Prokarium is taking a different approach to NMIBC therapy: retaining the proven immuno-stimulatory effects of bacterial immunotherapy but designing the treatment to be more convenient, with less frequent dosing due to an extended duration of action. This is also a better fit for how NMIBC is actually managed, as quarterly dosing aligns with existing disease monitoring to fit seamlessly into current urology practice.

Prokarium’s lead product is ZH9, a live strain of Salmonella enterica Typhi that harbours two attenuating mutations and has proven to be safe in extensive prior clinical evaluations in healthy volunteers. ZH9 is administered locally to the bladder similarly to BCG (and most other NMIBC treatments) but offers efficacy with far fewer doses due to a stronger, broader and more durable immune response [6]. ZH9 is also straightforward to manufacture and can easily be scaled up to meet demand.

Preclinically, ZH9 induces robust survival benefit against primary tumors following just a single dose in orthotopic animal bladder cancer models and on recovery, protects against tumor re-growth in the bladder and at distal sites. This indicates generation of essential tumor-specific immune memory which could provide patients with durable protection from tumour recurrence and spread. Further preclinical evidence supports the synergistic combination use of checkpoint inhibitors with ZH9, a potentially important finding in light of recent positive clinical results for sasanlimab (anti-PD1 mAb) or durvalumab (antiPD-L1 mAb) plus BCG therapy to treat high-risk NMIBC [7][8].

As reported at the recent 2026 American Urological Association meeting in Washington DC, the preclinical promise of ZH9 is now supported by clinical data [9]. In a phase 1/1B study (PARADIGM-1), intravesical ZH9 administration was well tolerated in NMIBC patients, with adverse event rates amongst the best (i.e. lowest) in field, reflecting no dose limiting toxicities and no grade three or higher adverse events related to the treatment, even after 4 doses. Whilst this is a small, safety focused study, early indications of efficacy further suggest class-leading freedom from relapse rates at 12 months of 91% (10/11 subjects per protocol completion; intention to treat population 67%; interim analysis). Importantly, the study included highly recurrent and heavily pre-treated subjects that had received a median of 2 prior standard-of-care BCG regimens. This early clinical promise, which was observed across both papillary tumour recurrence and carcinoma in situ (CIS) responses, combined with a mechanism of action complementary to existing approved therapies, points to the potential for broad use across the various bladder cancer patient subsets.

The future beyond ZH9

The outlook for bacterial immunotherapies in bladder cancer and beyond is bright. As demonstrated by Prokarium’s positive clinical data in NMIBC, bacteria’s inherent immunostimulatory properties alone can yield potent anti-tumor activity. Future generations have the potential to go even further, combining this intrinsic activity with the ability to deliver therapeutic payloads directly to the site of the tumor.

Tumor targeting is an inherent feature of some bacterial species, including Salmonella enterica. Academic groups worldwide have demonstrated that bacteria can not only preferentially localise to tumors but can also be engineered to sense and respond to features of the tumour microenvironment, bacterial density, exogenous drugs and physical stimuli. Engineered genetic circuits can translate these cues into the controlled delivery of a wide range of therapeutic molecules, enabling direct tumor-cell killing or orchestration of the anti-tumour immune response [10]. Payload-delivering bacteria therefore have the potential to overcome many of the delivery and toxicity challenges associated with existing immunotherapies and could even be designed to specifically complement other advanced cell therapies [11].

Prokarium’s next generation of therapies, Living Cures, builds on the safety and efficacy of its ZH9 Salmonella chassis by incorporating the programmable delivery of therapeutic payloads such as cytokines. Cytokines can be extraordinarily powerful immune activators, but systemic administration can cause serious toxicity. Engineering bacteria to produce these molecules only where and when they are needed creates the possibility of concentrating the therapeutic signal in the tumor while limiting exposure elsewhere. Prokarium is exploring a range of bacteria-optimised immune-modulatory payloads, including IL-15, decoy-resistant IL-18, IL-21 and CXCL9. These molecules act on key components of the anti-tumor immune response, including cytotoxic CD8+ T cells and NK cells, and may be deployed individually or jointly from the same bacterial strain to exploit their natural biological synergies.

By bringing together tumour targeting, sensing functions and localised payload delivery in chromosomally integrated genetic circuits, the Living Cures platform aims to enable a new generation of precision bacterial therapies capable of driving potent and durable anti-tumour responses.

Outlook

BCG has shown that bacteria can be effective cancer therapies. There is now the opportunity to build on this foundation using contemporary synthetic biology tools to effectively treat a wide range of solid tumors with high unmet need.

For Prokarium, bladder cancer is the starting point: a disease where bacterial immunotherapy is already clinically validated, but where treatment burden and recurrence leave considerable room for improvement. ZH9 is designed to combine the proven biology of bacterial immunotherapy with a stronger and more durable immune response to deliver a treatment designed for real-world urology practice.

The broader opportunity for Prokarium’s Living Cures platform, and the field, is to move beyond the intrinsic anti-tumor activity of bacteria and to create programmable treatments capable of sensing and responding to disease and delivering the right therapeutic molecules where and when they are needed. In doing so, programmable bacteria have the potential to become a new pillar of cancer therapy.

References
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  2. CANCER RESEARCH UK. (2026) Survival for bladder cancer. [Online] Available from: https://www.cancerresearchuk.org/about-cancer/bladder-cancer/survival [Accessed 11 August 2026].
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Nick Glanville, PhD, VP of Research at Prokarium
Nick Glanville
VP of Research at 

Nick Glanville, PhD, is VP of Research at Prokarium, a clinical-stage biopharmaceutical company pioneering bacterial immunotherapies for solid tumours.

Livija Deban, PhD, Chief Scientific Officer at Prokarium
Livija Deban
Chief Scientific Officer at 

Livija Deban, PhD, is Chief Scientific Officer at Prokarium, a clinical-stage biopharmaceutical company pioneering bacterial immunotherapies for solid tumours.

Dara Henry, PhD, Chief Operating Officer at Prokarium
Dara Henry
Chief Operating Officer at 

Dara Henry, PhD, is Chief Operating Officer at Prokarium, a clinical-stage biopharmaceutical company pioneering bacterial immunotherapies for solid tumours.