New oral cancer vaccine passes phase I safety study

A research group including Professor Toshiro Shirakawa of the Graduate School of Science, Technology and Innovation and Professor Hideaki Miyake and Dr. Hideto Ueki of the Graduate School of Medicine at Kobe University conducted a Phase I investigator-initiated clinical trial of the oral cancer vaccine B440 in patients with metastatic urothelial carcinoma whose disease had progressed after standard treatment. They confirmed the safety of B440 monotherapy and a WT1-specific T-cell response. B440 is an oral cancer vaccine aiming to deliver the cancer antigen WT1 to the gut immune system using bifidobacteria, which are closely involved in activating gut immunity. The findings were published in JCO Oncology Advances.

Immune checkpoint inhibitors have significantly changed the treatment of advanced cancers, such as those at Stage IV. However, only a subset of patients achieves sufficient therapeutic efficacy, and options remain limited after developing treatment resistance. There is a demand for developing therapies that safely boost the body's existing anti-cancer immune response to complement the efficacy of immune checkpoint inhibitors.

Focusing on bifidobacteria which is closely involved in gut immunity activation, the research group had been developing B440, which presents the WT1 antigen to the gut immune system by applying bifidobacteria as a delivery vector for antigen proteins.

In this study, they conducted a multicenter, open-label, single-arm Phase I investigator-initiated trial in patients with metastatic urothelial carcinoma whose disease had progressed after standard treatment. The trial included 12 patients with a history of treatment with PD-1/PD-L1 inhibitors or enfortumab vedotin. B440 was administered orally at 800 mg or 1,600 mg once daily, five days a week, for four weeks. The primary end point was the evaluation of dose-limiting toxicity (DLT) during the 28 days following the start of administration.

As a result, no dose-limiting toxicities were observed in either dose group. Adverse events judged to be related to B440 occurred in three patients, all being Grade 1 IL-6 elevation, and there were no treatment discontinuations due to B440-related adverse events. Regarding anti-tumor efficacy, stable disease was observed in six cases, progressive disease in five cases, and one case was unevaluable. No complete response or partial response was observed.

In the evaluation of immune responses, a WT1-specific T-cell response was detected by ELISPOT in 6 out of 12 patients. In these patients, a tendency toward prolonged progression-free survival compared to ELISPOT-negative cases was exploratorily observed.

After completion of the trial, re-administration of pembrolizumab was performed in some patients based on the judgment of their attending physicians, and tumor shrinkage was confirmed in certain cases. This re-administration was an exploratory observation outside the trial protocol and involves limitations such as selection bias. It cannot be concluded that B440 restored responsiveness to immune checkpoint inhibitors. Verification in prospective, pre-designed trials will be necessary.

These results highlighted several specific challenges for advancing the clinical development of B440 to the next stage. First, objective response (a certain level of tumor shrinkage) was not observed with B440 monotherapy. Combination or sequential administration with immune checkpoint inhibitors must be verified in prospective trials. Second, whether the WT1-specific immune response detected by ELISPOT can be used for patient selection or predicting efficacy needs to be confirmed in a larger population. Third, optimization of the treatment schedule, including administration duration, additional doses, and effects on the gut microbiota, needs to be pursued.

Currently, Kobe University, Hyogo Medical University, and other institutions are conducting an investigator-initiated trial combining B440 with an immune checkpoint inhibitor in patients with unresectable malignant pleural mesothelioma. Through such clinical trials, they will continue to carefully verify the efficacy, safety, appropriate administration methods, and indicators for patient selection for B440.

Journal Information
Publication: JCO Oncology Advances
Title: Phase I Study of B440, an Oral Wilms' Tumor 1 Cancer Vaccine Using a Bifidobacterium Vector, in Patients With Metastatic Urothelial Cancer
DOI: 10.1200/OA-25-00153