title: IL-15 augments antitumoral activity of an ErbB2/HER2 cancer vaccine targeted to professional antigen-presenting cells.
abstract: Targeted delivery of tumor-associated antigens to professional antigen-presenting cells (APC) is being explored as a strategy to enhance the antitumoral activity of cancer vaccines. Here, we generated a cell-based system for continuous in vivo production of a CTLA-4-ErbB2 fusion protein as a therapeutic vaccine. The chimeric CTLA-4-ErbB2 molecule contains the extracellular domain of CTLA-4 for specific targeting to costimulatory B7 molecules on the surface of APC, genetically fused to residues 1-222 of human ErbB2 (HER2) as an antigenic determinant. In wild-type BALB/c mice, inoculation of syngeneic epithelial cells continuously secreting the CTLA-4-ErbB2 fusion vaccine in the vicinity of subcutaneously growing ErbB2-expressing renal cell carcinomas resulted in the rejection of established tumors, accompanied by the induction of ErbB2-specific antibodies and cytotoxic T cells. In contrast, treatment with CTLA-4-ErbB2 vaccine-secreting producer cells alone was insufficient to induce tumor rejection in ErbB2-transgenic WAP-Her-2 F1 mice, which are characterized by pronounced immunological tolerance to the human self-antigen. When CTLA-4-ErbB2 producer cells were modified to additionally secrete interleukin (IL)-15, antigen-specific antitumoral activity of the vaccine in WAP-Her-2 F1 mice was restored, documented by an increase in survival, and marked inhibition of the growth of established ErbB2-expressing, but not antigen-negative tumors. Our results demonstrate that continuous in vivo expression of an APC-targeted ErbB2 fusion protein results in antigen-specific immune responses and antitumoral activity in tumor-bearing hosts, which is augmented by the pleiotropic cytokine IL-15. This provides a rationale for further development of this approach for specific cancer immunotherapy.
authors.affiliation: Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Straße 42-44, 60596 Frankfurt am Main, Germany.
authors.forename: Ute E
authors.initials: UE
authors.lastname: Burkhardt
authors.forename: Arjen
authors.initials: A
authors.lastname: Sloots
authors.forename: Vera
authors.initials: V
authors.lastname: Jakobi
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.forename: Björn-Philipp
authors.initials: BP
authors.lastname: Kloke
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active; D019409:Interleukin-15 / Q000276:immunology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D019409:Interleukin-15; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C556706:CTLA4 protein, human