title: Induction of anti-tumor immunity by trifunctional antibodies in patients with peritoneal carcinomatosis.
abstract: Peritoneal carcinomatosis (PC) from epithelial tumors is a fatal diagnosis without efficient treatment. Trifunctional antibodies (trAb) are novel therapeutic approaches leading to a concerted anti-tumor activity resulting in tumor cell destruction. In addition, preclinical data in mouse tumor models demonstrated the induction of long lasting tumor immunity after treatment with trAb. We describe the induction of anti-tumor specific T-lymphocytes after intraperitoneal administration of trAb in patients with PC.9 patients with progressive PC from gastric (n = 6) and ovarian cancer (n = 2), and cancer of unknown primary (n = 1) received 3 escalating doses of trAb after surgery and/or ineffective chemotherapy. The trAb EpCAM x CD3 (10, 20, 40 microg) or HER2/neu x CD3 (10, 40, 80 microg) were applicated by intraperitoneal infusion. Four weeks after the last trAb application, all patients were restimulated by subdermal injection of trAb + autologous PBMC + irradiated autologous tumor cells. Immunological reactivity was tested by analyzing PBMC for specific tumor reactive CD4+/CD8+ T lymphocytes using an IFN-gamma secretion assay.In 5 of 9 patients, tumor reactive CD4+/CD8+ T-lymphocytes increased significantly, indicating specific anti-tumor immunity. A clinical response (stable disease, partial regression) has been observed in 5 of 9 patients, with a mean time to progression of 3.6 months. Follow-up showed a mean survival of 11.8 months (median 8.0 months) after trAb therapy.TrAb are able to induce anti-tumor immunity after intraperitoneal application and restimulation. The induction of long-lasting anti-tumor immunity may provide an additional benefit of the intraperitoneal therapy with trAb and should be further elevated in larger clinical trials.
authors.affiliation: Department of Abdominal, Vascular and Transplant Surgery, Campus Cologne-Merheim, Witten/Herdecke University, Ostmerheimer Str, 200, 51109 Cologne, Germany. stroehleinm@kliniken-koeln.de
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ströhlein
authors.forename: Robert
authors.initials: R
authors.lastname: Siegel
authors.forename: Michael
authors.initials: M
authors.lastname: Jäger
authors.forename: Horst
authors.initials: H
authors.lastname: Lindhofer
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heiss
mesh_terms: D000328:Adult; D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010865:Pilot Projects; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; C511895:ertumaxomab; C522419:catumaxomab