title: Combining bacterial-immunotherapy with therapeutic antibodies: a novel therapeutic concept.
abstract: Immunotherapeutic strategies become more and more important for cancer treatment. Therapeutic monoclonal antibodies (mAbs) like Panitumumab binding and blocking the EGF-receptor are in routine clinical use for the treatment of colorectal carcinoma (CRC). Also, bacterial therapy proved beneficial for experimental treatment of different tumor entities. The latter has been attributed to an activation of the immune system. Here, we describe a combination of both immunotherapeutic approaches in order to develop a novel targeted therapy for CRC. The therapeutic mAbs Trastuzumab and Panitumumab were conjugated to heat-inactivated bacteria expressing protein A or protein G. The potential of the conjugates was tested in comparison to the single components both in vitro and in vivo using a panel of patient-derived CRC cell lines. Antitumoral effects observed in vitro were strictly dependent on the presence of bacteria. Generally, effects could be enhanced by the addition of human lymphocytes. Detailed analysis of effector cells in autologous and allogeneic long-term stimulated lymphocyte cultures revealed the predominance of NK-cell-like cytolytic effectors. Reactivity was observed both against CRC target cells but also against the NK cell target K562. Similarly, in a subsequent in vivo study we observed substantial tumor growth delay accompanied by an increase in circulating NK cells. Contrary to this, the monotherapy with mAb alone caused only marginal effects and the treatment with bacteria was comparable to the mock-treated control. These data demonstrate successful targeting of CRC by bacteria/mAb conjugates. This novel concept may be interesting for future clinical approaches. Additionally, it illustrates the effectiveness of NK cells for cancer immunotherapy.
authors.affiliation: Department of General, Vascular, Thoracic and Transplantation Surgery, Section of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Klier
authors.forename: Claudia
authors.initials: C
authors.lastname: Maletzki
authors.forename: Bernd
authors.initials: B
authors.lastname: Kreikemeyer
authors.forename: Ernst
authors.initials: E
authors.lastname: Klar
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use*; D001419:Bacteria / Q000737:chemistry / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000077544:Panitumumab; D000068878:Trastuzumab; D018074:Vaccines, Conjugate; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019496:Cancer Vaccines; D018074:Vaccines, Conjugate; D000077544:Panitumumab; D000068878:Trastuzumab