Professor Kobe University Graduate School of Science, Technology and Innovation
Introduction: Cancer immunotherapy with immune-checkpoint inhibitors (ICIs) including PD-1/PD-L1 inhibitors has been well established for various types of cancer including bladder cancer. Monotherapy with ICIs, however, can achieve a durable response in only a subset of patients. There is a great unmet need for ICI-resistant tumors. Although combining ICIs with cancer vaccines which forcibly induce an antitumor T cell response is a reasonable strategy, the preferred administration sequence is unknow. In our previous study, we demonstrated that an oral cancer vaccine, a recombinant Bifidobactrerium (B.) longum displaying a WT1 tumor associated antigen, inhibited the tumor growth in a TRAMP-C2 mouse prostate cancer tumor model and that its anti-tumor activity could be augmented by an anti-PD-1 antibody (Molecular Cancer Therapeutics, 2019;18:980-). In the present study we explored the feasibility of this oral vaccine in a mouse syngeneic bladder cancer model.
Methods: A recombinant B. longum 420 strain that expresses partial murine-WT1 protein fused to galacto-N-biose/lacto-N-biose I binding protein, which we used as an anchor to display antigen on the bacterial cell surface, was constructed. MBT-2, which is a bladder cancer cell line originated from C3H/He mice and endogenously expresses WT1 protein, was used to generate a syngeneic subcutaneous tumor model. Mice were orally administered 1.0×109 colony-forming units of B. longum 420, 5 times a week for 5 weeks, using a feeding needle. For an anti-PD-1 antibody treatment, 200µg of anti-PD-1 antibody was intraperitoneally injected into mice twice a week for 2 weeks. Tumors continuously grew despite the initial anti-PD-1 treatment were selected as the anti-PD-1 antibody-resistant tumor. In addition, immunological responses including tumor-infiltrating lymphocytes (TILs) were thoroughly analyzed.
Results: Combining B. longum 420 and following anti-PD-1 antibody treatment completely suppressed the MBT-2 tumor growth and cured all mice tested, while all anti-PD-1 antibody treated mice died. The significantly increased CD4 and CD8 positive T cells were observed in the TILs of combination treatment group. Moreover, in the anti-PD-1 antibody-resistant tumor model, this vaccine alone significantly inhibited the tumor growth, while combination with continuous anti-PD-1 antibody could not inhibit the tumor growth. Interestingly, the number of regulatory T cells in TILs of the vaccine alone group was significantly smaller than the combination treatment group.
Conclusions: These results suggest that this oral cancer vaccine alone or as an adjunct to anti-PD-1 antibody could provide a novel treatment option for patients with advanced bladder cancer.
Source of Funding: Japan Agency for Medical Research and Development (AMED): 20lm0203091h0002.