Antibody Could Be Used to Target Tumor-Enhancing Protein, Study Shows
In a phase I study published in PLOS ONE, treating patients with advanced melanoma and kidney cancer with an antibody that targets a tumor-enhancing protein was found to have an acceptable safety profile and showed preliminary evidence of antitumor activity. The findings by Morris et al shed light on a therapy that could be used alone or in combination to treat a number of cancers.
Targeting TGF-β
Transforming growth factor–beta (TGF-β) is a protein that promotes tumor growth metastases and suppresses host antitumor immunity in advanced cancers. "[TGF-β] helps cells maintain their functions, from formation to transition to death,” said principal investigator John Morris, MD, of the Cincinnati Cancer Center and UC Cancer Institute. "Early in the transition of cancers from premalignancy to malignancy, TGF-β can suppress cell growth; however, in advanced cancers, these effects are typically lost, and TGF-β will directly promote the growth and spread of tumors,” he added.
“Increased TGF-β has been reported in many different cancers including prostate, breast, lung, pancreatic, renal cell, … liver, and more, and elevated plasma TGF-β levels correlate ith advanced tumor stage, metastases, and poor survival. Given this data, the protein is being examined for potential therapeutic targets,” Dr. Morris said.
He added that in preclinical models, antibodies or receptors that hinder TGF-β have shown antitumor activity. When used in combination with chemotherapy, radiation, or other biologic treatments, anti–TGF-β antibodies have been reported to improve the treatment of both primary and metastatic disease in animal models.
GC1008 (also known as fresolimumab), is a human antibody that neutralizes all isoforms of human TGF-β. The current study was designed to test the safety and efficacy of this treatment in repeated doses in patients with malignant melanoma and renal cell carcinoma.
Study Details
In the study, which was conducted at the National Cancer Institute and a number of cancer centers in the United States, patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at varying doses. Patients who were stabilized, with no progression of the cancer, were eligible to receive extended treatment consisting of four doses of GC1008 every 2 weeks for up to two additional rounds. Pharmacokinetic and exploratory biomarker assessments were performed.
A total of 29 patients (28 with malignant melanoma and 1 with renal cell carcinoma) were enrolled in the study and treated, 22 in the dose-escalation cohort and 7 in a safety cohort expansion. No dose-limiting toxicities were observed, and the maximum dose (15 mg/kg) was determined to be safe.
One patient with malignant melanoma experienced a partial positive response to treatment, and six had stable disease. These seven patients had a median progression-free survival of 24 weeks (range, 16.4–44.4 weeks). Four patients developed reversible squamous cell carcinoma, which was the major adverse event observed.
GC1008 was shown to have an acceptable safety profile when administered at up to 15 mg/kg every 2 weeks. “This preliminary evidence of antitumor activity indicates that additional studies are needed to help determine the efficacy and safety of GC1008 alone and in combination with other treatments, as well as define dose and response,” said Dr. Morris.
Dr. Morris and Jay A. Berzofsky, MD, PhD, of the Center for Cancer Research, National Cancer Institute, are the corresponding authors for the PLOS ONE study.
The study was funded by Genzyme Corporation and the National Cancer Institute. Dr. Morris reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
