Phase I Study of B440, an Oral Wilms' Tumor 1 Cancer Vaccine Using a Bifidobacterium Vector, in Patients With Metastatic Urothelial Cancer

PURPOSE Immune checkpoint inhibitors (ICIs) demonstrate limited efficacy in metastatic urothelial cancer (mUC), with most patients eventually developing resistance. B440 is an oral cancer vaccine composed of recombinant Bifidobacterium engineered to express the Wilms' tumor 1 (WT1) tumor-associated antigen, designed to elicit tumor-specific T-cell responses via gut-associated lymphoid tissue. This phase I study evaluated the safety, preliminary efficacy, and immunogenicity of B440 in patients with mUC refractory to standard therapies. METHODS Twelve patients with mUC who had progressed after platinum-based chemotherapy, PD-1/PD-L1 inhibitors, and enfortumab vedotin received oral B440 at either 800 mg (n = 6) or 1,600 mg (n = 6) once daily for five consecutive days per week over 4 weeks. The primary end point was dose-limiting toxicity (DLT). Secondary end points included safety, best overall response, and progression-free survival (PFS). WT1-specific T-cell responses were assessed via interferon-γ enzyme-linked immunospot (ELISPOT) assays. Fecal samples were collected for gut microbiome analysis. RESULTS No DLTs were observed. Treatment-related adverse events were mild (grade 1), with transient IL-6 elevations reported in three patients. The disease control rate was 50%, with six patients achieving stable disease. WT1-specific T-cell responses were detected in six patients, who showed numerically longer PFS than ELISPOT-negative patients (117 v 37 days; nominal P = .030, uncorrected for multiple comparisons). Changes in gut microbiome diversity showed exploratory associations with clinical outcomes. CONCLUSION B440 was safe and well tolerated. WT1-specific immune responses correlated with clinical benefit, supporting further investigation of B440 in combination immunotherapy trials.