The most powerful cancer immunotherapies come with a cruel paradox. CAR-T cell therapies and bispecific antibodies can send advanced blood cancers into remission, but they trigger a systemic inflammatory storm in more than 70% of patients. Cytokine release syndrome, or CRS, can turn a lifesaving treatment into an ICU emergency: high fevers, crashing blood pressure, multi-organ failure. There is no approved drug to prevent it.
A London-based clinical-stage biopharmaceutical company, Poolbeg Pharma, is now testing whether a single oral pill can change that. The company announced this month that the first clinical site has been activated for the TOPICAL trial (Trial of Prevention of ImmunoCytokine Adverse events in Myeloma), a randomised, placebo-controlled Phase IIa study evaluating POLB 001 in patients with relapsed or refractory multiple myeloma receiving the approved bispecific antibody teclistamab (Tecvayli, Johnson & Johnson).
The Engine of the Storm
CRS is caused by a rapid, uncontrolled release of pro-inflammatory cytokines, TNF-α, IL-6, IL-8, IL-1β, and others, triggered when immune cells activated by CAR-T or bispecific therapy suddenly expand and degranulate. The condition ranges from mild (fever, fatigue) to life-threatening (hypotension, capillary leak, respiratory failure). Current management relies on the IL-6 receptor antibody tocilizumab (Actemra) and high-dose corticosteroids, both reactive, not preventive.
POLB 001 takes a different approach. It is an oral, small-molecule inhibitor of p38α/β MAPK, a central signalling node in the inflammatory cascade. By blocking p38 MAPK activation, the drug reduces production of multiple cytokines simultaneously, rather than targeting just IL-6 after the storm has already begun.
Poolbeg’s Chief Investigator, Dr Emma Searle, Consultant Haematologist at The Christie NHS Foundation Trust in Manchester, describes the strategic logic: “If we can prevent CRS from happening in the first place, we could potentially administer these highly effective therapies in an outpatient setting, which would transform patient care.”
From LPS to Teclistamab
The clinical foundation for POLB 001 comes from a Phase 1 randomised, double-blind, placebo-controlled trial published in Frontiers in Immunology in January 2026. In that study, 36 healthy volunteers received POLB 001 at doses of 30, 70, or 150 mg twice daily for seven days, followed by a lipopolysaccharide (LPS) challenge, a standard human model of systemic inflammation.
The results were striking. After intravenous LPS challenge, POLB 001 reduced TNF-α by up to 73.5% (p=0.0003), IL-6 by up to 63.5% (p=0.0002), and IL-8 by up to 80.7% (p<0.0001). C-reactive protein fell by 33% at both the 70 mg and 150 mg doses (p<0.05). Target engagement was confirmed: p38 MAPK phosphorylation in CD14+ monocytes dropped by up to 60.9% in a dose-dependent manner (p<0.02).
Importantly, the drug did not suppress the immune system indiscriminately. In humanised mouse models of CRS, POLB 001 prevented symptoms while preserving the tumour-killing activity of co-administered immunotherapies, an effect confirmed in in vitro data presented at the European Haematology Association (EHA) 2026 Congress. The drug was well tolerated in the Phase 1 study, with no serious adverse events.
The TOPICAL Trial
The Phase IIa TOPICAL trial will recruit approximately 30 patients with relapsed or refractory multiple myeloma across six NHS hospitals:
- The Christie NHS Foundation Trust (Manchester)
- The Royal Marsden Hospital (London)
- University College London Hospitals
- University Hospitals Birmingham
- NHS Lothian (Edinburgh)
- Royal Stoke University Hospital (Stoke-on-Trent)
Patients will receive teclistamab, supplied free of charge by Johnson & Johnson, combined with either POLB 001 or placebo. The primary endpoint is the incidence and severity of CRS during the first cycle of treatment. The trial received Clinical Trial Authorisation from the UK’s Medicines and Healthcare products Regulatory Agency in April 2026.
The trial is funded in part by a £3.4 million Medical Research Council Prosperity Partnership grant, awarded to a collaboration between Poolbeg Pharma, the University of Manchester, and The Christie. Interim data are expected in summer 2026, with top-line results anticipated in the second half of the year.
A Market with No Entrants
No preventative therapy for CRS is currently approved anywhere in the world. Independent US payer research commissioned by Poolbeg estimates multi-billion dollar peak sales potential, driven in part by the cost of managing a single Grade 3 CRS episode, which exceeds $70,000. A prophylactic oral drug that could shift these therapies from hospital to outpatient administration would have significant economic as well as clinical implications.
Regulatory momentum is building. The US Food and Drug Administration granted POLB 001 Orphan Drug Designation for the prevention of bispecific antibody-induced CRS in May 2025. Patents covering the drug’s use in hypercytokinaemia have been granted in the US (2024), Australia, and Canada, with protection that could extend to at least 2044.
The Caveats
The TOPICAL trial is small, 30 patients, and Phase IIa is primarily designed to detect a safety signal and efficacy signal, not to deliver a definitive answer. The study is restricted to multiple myeloma patients receiving teclistamab, so results may not generalise to other bispecific antibodies or CAR-T products without further trials.
The Phase 1 data were generated in healthy volunteers using an LPS challenge, a reasonable model of systemic inflammation, but not the same as real CRS in cancer patients. Whether the cytokine reductions seen in the lab translate into clinically meaningful CRS prevention will not be known until the TOPICAL data are read out.
Dr Jonathan Lim, Clinical Senior Lecturer at the University of Manchester and an investigator on the trial, struck a measured tone: “This is an important step, but it is just the beginning. We need to see whether the preclinical and Phase 1 promise holds up in the real patient population, where the stakes are much higher.”
What’s Next
Poolbeg CEO Dr Jeremy Skillington has indicated the company is already looking beyond multiple myeloma. Early data presented at EHA 2026 suggest potential applications in acute myeloid leukaemia, and the company’s pipeline strategy envisions POLB 001 as a platform therapy for immunotherapy-induced CRS across indications.
If the TOPICAL trial delivers positive results, the implications extend beyond a single drug. A safe, oral prophylactic for CRS could change the risk-benefit calculus for CAR-T and bispecific therapies, allowing earlier use, outpatient administration, and wider patient access. For the tens of thousands of patients whose cancer immunotherapy is currently limited by the fear of the storm, that would be more than a commercial opportunity, it would be a clinical transformation.
Sources:
1. Poolbeg Pharma. “TOPICAL Trial: First Clinical Site Activated.” Company announcement, June 2026. https://www.poolbegpharma.com/
2. Poolbeg Pharma. “POLB 001 Pipeline, Oncology.” https://www.poolbegpharma.com/pipeline/polb-001-oncology/
3. Morris, T. et al. “POLB 001, a selective p38 MAPK inhibitor, reduces systemic and local inflammation in a human LPS challenge model.” Frontiers in Immunology, January 2026. DOI: 10.3389/fimmu.2025.1684307
4. The Guardian. “London startup to trial drug to prevent cancer therapy side-effect ‘cytokine storm’.” June 14, 2026. https://www.theguardian.com/business/2026/jun/14/london-trial-drug-prevent-cancer-cytokine-storm-poolbeg-pharma
5. Poolbeg Pharma. EHA 2026 Congress poster presentation, POLB 001 preserves tumour-killing activity while inhibiting CRS cytokines, May/June 2026.
6. Acumetis Global. Independent US payer research, POLB 001 market assessment, 2026.