MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate
immunotherapy product for the treatment of
prostate cancer. It encodes 2
tumor-associated
antigens,
prostate-specific antigen (PSA), and
prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified
vaccinia Ankara (MVA) virus stock known as
MVA-BN. Past work has shown that the immunogenicity of
antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the
antigen to the C1C2 domain of the lactadherin
protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of
MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with
MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with
MVA-BN-PRO. These improvements translated into a greater frequency of
tumor rejection in a PAP-expressing solid
tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with
MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing
tumor model. These experiments confirm that targeting
antigen localization to exosomes is a viable approach for improving the therapeutic potential of
MVA-BN-PRO in humans.