@article{5221e026330c476bbde144d981b030da,
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.",
keywords = "Anti-tgfβ antibody, Antibody therapy, Clinical trial, Gc1008, Immunotherapy, Malignant mesothelioma",
author = "Stevenson, {James P.} and Kindler, {Hedy L.} and Emmanouil Papasavvas and Jing Sun and Mona Jacobs-Small and Jennifer Hull and Daniel Schwed and Anjana Ranganathan and Kheng Newick and Heitjan, {Daniel F.} and Langer, {Corey J.} and McPherson, {John M.} and Montaner, {Luis J.} and Albelda, {Steven M.}",
note = "Funding Information: The study was primarily funded by the Richard Schulze Family Foundation; additional support was provided by grants P30-CA016520 (DFH, SMA, MJ-S), the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health and Cancer Center Grant (P30 CA10815) (LJM and EP) and an NIEHS funded Environmental Health Sciences Core Center grant P30-ES013508 (SMA). The authors wish to thank: (1) Dr. Frank Hsu, Dr. Scott Lonning, Joan Mannick, Eileen Budri, Cliff Hendrick, and Michael Menconi of Genzyme Corporation for administrative, regulatory, and biomarker analysis support; (2) Dr. Guanjun Cheng at Penn for technical support; (3) Jocelin Joseph, Charity Calloway, Brian Ross, Agnieszka Mackiewicz at the Wistar Institute for technical support; (4) Dr. Anil Vachani at Penn for providing control serum; (5) Drs. Carlos Paz, Brian Pucevich, Vesna Petronic-Rosic, and Maria Tsoukas at the University of Chicago for assistance in interpreting the skin pathology; and Fujirebio Inc. for the SMRP ELISA kits. Funding Information: Trial design. This trial was designed as a 40 patient two-center (University of Pennsylvania and University of Chicago), open-label, Phase II trial for patients with relapsed MPM. The ClinicalTrials.gov registration number is NCT01112293. The original objectives were the determination of progression-free survival (PFS) at 3 mo, as well as toxicity and safety of GC1008 in pretreated MPM patients. Secondary endpoints included radiographic response assessment and overall survival (OS). Laboratory objectives included identification of biomarkers of effects of TGFβ blockade and assessment of immune responses against the tumor. The protocol was approved by the University of Pennsylvania Medical Center and University of Chicago Institutional Review Boards and the Food and Drug Administration. Written informed consent, in accordance with the Declaration of Helsinki protocols, was obtained from each patient at the time of screening. An independent safety monitor reviewed safety data after the first three subjects were enrolled. The study was sponsored by the University of Pennsylvania and was funded primarily by the Richard Schulze Family Foundation.",
year = "2013",
doi = "10.4161/onci.26218",
language = "English (US)",
volume = "2",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "8",
}