Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients

Our plain-English summary of Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients, by J.P. Stevenson, H.L. Kindler, E. Papasavvas, et al (Oncoimmunology, 2013).

The study

• Authors: J.P. Stevenson, H.L. Kindler, E. Papasavvas, J. Sun, M. Jacobs-Small, J. Hull, D. Schwed, A. Ranganathan, K. Newick, D.F. Heitjan, C.J. Langer, J.M. McPherson, L.J. Montaner, S.M. Albelda
• Journal: Oncoimmunology
• Published: 2013;2(8):e26218
• Cited by: 68 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This open-label Phase II trial tested GC1008 (fresolimumab), a TGFβ-blocking antibody, in patients with previously treated, progressing malignant pleural mesothelioma. Planned for 40 patients, it stopped after 13 when the manufacturer ended the drug's cancer development. Patients received 3 mg/kg intravenously every three weeks. The study did not examine asbestos exposure. No partial or complete tumor responses were seen on scans. Three of 13 (23%) went 3 months without progression; median overall survival was 12 months. Grade 3 or 4 side effects were nausea, constipation and ileus, one patient each. One patient's tumor grew unusually fast; the authors questioned whether the drug accelerated it. Another developed penile lesions; site and central pathologists diagnosed squamous cell carcinoma and atypical keratoacanthoma, respectively. Five of 13 patients developed new or stronger antibodies against mesothelioma cell extracts. Their median survival was 15 months, versus 7.5 months for the other 8 (p = 0.03). The authors judged the drug generally well tolerated and said antibody responses may be associated with longer survival. They said the small number of patients prevented definitive conclusions about efficacy and safety.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two-center, open-label Phase II clinical trial, designed for 40 patients but ended after 13 were enrolled
• Who was studied: 13 patients with malignant pleural mesothelioma that had progressed after one or two prior systemic therapies, at least one containing pemetrexed. There were 11 males and 2 females, median age 69 (range 46 to 81). Seven were treated at the University of Pennsylvania and 6 at the University of Chicago. Eleven had epithelial histology, 1 biphasic and 1 sarcomatoid. Six healthy control subjects matched for age, gender and smoking were used for the immune cell comparisons. Enrollment dates are not given.
• Exposure: Treatment with GC1008 (fresolimumab), a human monoclonal antibody that neutralizes TGFβ, given at 3 mg/kg intravenously every three weeks. Asbestos exposure was not studied.
• Main results:
  • No partial or complete radiographic responses were seen in the 13 patients.
  • Three of 13 patients (23%) met the primary objective of 3 months without disease progression, with times to progression of 4.1, 4.2 and 9 months. All 3 had stable disease.
  • Among all 13 patients, median time to progression was 1.4 months and median overall survival was 12 months.
  • Grade 3 or 4 toxicities were nausea, constipation and ileus, in 1 patient each.
  • In one patient the tumor grew rapidly after GC1008. The authors said this raises the question of whether the drug accelerated progression in that case; they did not establish that it did.
  • A 77-year-old man developed lesions on the penis after 5 doses. Site pathologists diagnosed squamous cell carcinoma, and the trial's central pathologist diagnosed atypical keratoacanthoma.
  • Mean baseline plasma TGFβ in patients was 2447 pg/ml, compared with an average of 1051 pg/ml in normal subjects. TGFβ levels fell markedly after treatment. The other blood markers tested showed no consistent change.
  • Serum from 5 of the 13 patients showed new or enhanced antibodies against mesothelioma tumor lysates. No patient developed antibodies against mesothelin, SV40 T-antigen or osteopontin.
  • Median overall survival was 15 months in the 5 patients who produced anti-tumor antibodies and 7.5 months in the 8 who did not (p = 0.03).
  • In the 10 patients with usable blood cell samples, GC1008 did not change most NK cell and T cell markers. The exceptions were significant decreases in 2B4 (16.1% to 10.1% of NK cells, p = 0.02) and DNAM1 (96.6% to 93.2%, p = 0.02).
  • Regulatory T cells made up 8.7% of CD4+ T cells in the 6 controls and 4.8% in mesothelioma patients before treatment (p less than 0.001). There was no significant change after GC1008.
• The authors' conclusion: The authors concluded that GC1008 was generally well tolerated in previously treated MPM patients, but that TGFβ blockade might support the growth of susceptible premalignant or malignant cells in a minority of subjects. They also said their data are consistent with TGFβ blockade leading to anti-tumor immune responses in some patients, and that such immunity may be associated with increased survival.
• Limitations the authors state:
  • Only 13 patients were enrolled, which the authors say precluded definitive conclusions about clinical efficacy and safety.
  • No tumor samples were available after treatment.
  • The finding of lower regulatory T cell levels in patients than in controls needs to be validated in a larger cohort.
  • More patients given long-term TGFβ blockade would be needed to know how often tumor-accelerating events occur.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Mesothelioma, Biomarker, Median Overall Survival.

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