title: Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients.
abstract: We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1-2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
authors.affiliation: Penn Mesothelioma and Pleural Program; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Papasavvas
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Mona
authors.initials: M
authors.lastname: Jacobs-Small
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hull
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwed
authors.forename: Anjana
authors.initials: A
authors.lastname: Ranganathan
authors.forename: Kheng
authors.initials: K
authors.lastname: Newick
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: John M
authors.initials: JM
authors.lastname: McPherson
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
keywords: GC1008; anti-TGFβ antibody; antibody therapy; clinical trial; immunotherapy; malignant mesothelioma