title: Exosome targeting of tumor antigens expressed by cancer vaccines can improve antigen immunogenicity and therapeutic efficacy.
abstract: 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.
authors.affiliation: Department of Research and Development, BN ImmunoTherapeutics, Mountain View, CA, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Mandl
authors.forename: James M
authors.initials: JM
authors.lastname: Nachtwey
authors.forename: Katie
authors.initials: K
authors.lastname: Dalpozzo
authors.forename: Lisa
authors.initials: L
authors.lastname: Do
authors.forename: John R
authors.initials: JR
authors.lastname: Lombardo
authors.forename: Peter L
authors.initials: PL
authors.lastname: Schoonmaker
authors.forename: Kay
authors.initials: K
authors.lastname: Brinkmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Dirmeier
authors.forename: Reiner
authors.initials: R
authors.lastname: Laus
authors.forename: Alain
authors.initials: A
authors.lastname: Delcayre
mesh_terms: D000135:Acid Phosphatase; D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D055354:Exosomes / Q000276:immunology*; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000276:immunology / Q000493:pharmacokinetics; D017430:Prostate-Specific Antigen / Q000008:administration & dosage / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; C098942:MFGE8 protein, human; C561498:MVA-BN-PAP-C1C2 vaccine; C561496:MVA-BN-PRO vaccine; C561497:MVA-BN-PSA-C1C2 vaccine; D008894:Milk Proteins; D014613:Vaccines, Attenuated; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D017430:Prostate-Specific Antigen