A Phase 1, First-in-human, Open Label, Dose Escalating Study of B440, an Oral Cancer Vaccine Using a WT1-expressing Bifidobacterium , in Patients with Advanced Urothelial Cancer.

TPS883 Background: B440, an oral cancer therapeutic vaccine, is based on an innovative oral vaccine platform utilizing gut microbiota ( B. longum; Bifidobacterium longum ) that can efficiently deliver the heterogeneous antigen protein to dendritic cells (DCs) in Peyer's patches in gut-associated lymphoid tissue (GALT). B440 is a lyophilized powder of inactivated B. longum 440, a recombinant B. longum expressing a partially modified human WT1 tumor-associated antigen protein (amino acids 117-419 with a single amino acid substitution at 236 from M to Y to enhance immunogenicity). In preclinical studies, B440 showed superior anti-tumor activity to the WT1 peptide vaccine (WT1 126-134 peptide, human HLA-A02 or mouse H-2Db restricted CD8 epitope) due to the large length of the WT1 117-419 protein, including multiple CD8 and CD4 epitopes without HLA restriction, and its ability to internalize into DCs (1, 2). Furthermore, our extensive preclinical studies showed that B440 alone or as an adjunct to an anti-PD1 antibody can induce potent WT1-specific cellular immunity and anti-tumor activity in several mouse syngeneic tumor models (urothelial cancer (3), prostate cancer (4), and renal cell carcinoma (5)). Methods: This first-in-human, multicenter, open-label, single-arm, investigator-initiated phase 1 study will evaluate the safety and initial efficacy of B440 monotherapy in patients with advanced urothelial cancer who are refractory to all standard therapies, including chemotherapeutic agents, PD-1/PD-L1 inhibitors and antibody-drug conjugates (ADCs). A total of 12 patients will receive B440 orally once daily for 5 consecutive days followed by a 2-day rest for a total of 20 doses for 4 weeks. The study consists of 2 escalating doses of 6 patients each; the low dose group will receive 800 mg (4 capsules) per dose and the high dose group will receive 1,600 mg (8 capsules) per dose. One enteric capsule contains 200 mg of B440, equivalent to 2X10 10 colony forming units (cfu) of B. longum 440. The primary endpoint is the determination of dose-limiting toxicity (DLT) with an assessment period of 4 weeks during treatment. Secondary endpoints are safety as assessed by adverse events (AEs) using CTCAE 5.0 and efficacy as assessed by best overall response and progression-free survival (PFS) using RECIST ver1.1. In addition, the immunological response to B440 will be evaluated by enzyme-linked immunosorbent assay (ELISPOT). The study was registered with the Japan Registry of Clinical Trials under the number jRCT2051220143 on December 27, 2022. Patient enrollment was completed in September 2024. Research Sponsor: Immunorock Co., Ltd., Grant: the Japan Agency for Medical Research and Development (AMED); 23ym0126081h0002. Clinical trial information: jRCT2051220143 .