Kitagawa et al. developed an oral vaccine of WT1 protein expressed on the surface of B. longum and observed improved T cell cytokine production, splenocyte proliferation, and cytotoxic activity upon vaccination and ex vivo WT1+ TRAMP-C2 cell stimulation compared to an i.p. peptide vaccine in mice. Combination with anti-PD-1 enhanced T cell tumor infiltration, slowed tumor growth, and improved survival. A human WT1 B. longum vaccine led to T cell responses in the mouse for two known human WT1 epitopes, and a lyophilized form of the vaccine showed comparable tumor growth inhibition at a range of dosing regimes.
Contributed by Alex Najibi
Previously, we constructed a recombinant Bifidobacterium longum displaying a partial mouse Wilms' tumor 1 (WT1) protein (B. longum 420) as an oral cancer vaccine using a bacterial vector and demonstrated that oral administration of B. longum 420 significantly inhibited tumor growth compared with the Db126 WT1 peptide vaccine in the TRAMP-C2, mouse castration-resistant prostate cancer (CRPC) syngeneic tumor model. The present study demonstrated that oral administration of 1.0X109 colony-forming units of B. longum 420 induced significantly higher cytotoxicity against TRAMP-C2 cells than intraperitoneal injection of 100 mug of Db126, and the in vivo antitumor activity of B. longum 420 in the TRAMP-C2 tumor model could be augmented by intraperitoneal injections of 250 mug of anti-PD-1 antibody. For the clinical development, we produced the B440 pharmaceutical formulation, which is lyophilized powder of inactivated B. longum 440 displaying the partially modified human WT1 protein. We confirmed that B. longum 440 could induce cellular immunity specific to multiple WT1 epitopes. In a preclinical dosage study, B440 significantly inhibited growth of the TRAMP-C2 tumors compared with that of the control groups (PBS and B. longum not expressing WT1) at all dosages (1, 5 and 10 mg/body of B440). These mouse doses were considered to correspond with practical oral administration doses of 0.2, 1 and 2 g/body for humans. Taken together, these results suggest that the B440 WT1 oral cancer vaccine can be developed as a novel oral immuno-oncology drug to treat CRPC as a monotherapy or as an adjunct to immune checkpoint inhibitors.