Guiding GC1008 Treatment of Primary Brain Tumors by 89Zr-GC1008 PET Imaging.

Brain tumors account for only 2% of all cancers but result in a disproportionate share of cancer morbidity and mortality. The five-year survival rates for the most common histologic subtypes, anaplastic astrocytoma and glioblastoma (glioblastoma multiforme, GBM), are 30% and 10%, respectively.

After surgery, the standard treatment of malignant glioma is focused on cell death induction by DNA damage, neglecting the fact that invasion into surrounding brain tissue is a fundamental feature of and the major reason for treatment failure.

Drugs affecting transforming growth factor-β (TGF-β) might be of great interest for malignant glioma treatment. The reason for this is the fact that TGF-β acts as a tumor suppressor in normal epithelial cells and early-stage tumors but transforms in an oncogenic factor in advanced tumors where it induces proliferation, angiogenesis, invasion, and metastasis as well as suppresses the antitumoral immune response. In addition TGF-β expression and its TGF-β receptors, TβRI and TβRII, are overexpressed in GBMs. TGF-β signaling is involved in multiple steps of GBM development (Golestaneh, Mishra, 2005) and invasion (Wesolowska et al, 2008). Plasma TGF-β levels are elevated in GBM patients and decrease after surgical tumor resection (Schneider et al, 2006). Progression-free survival and overall survival are worse for malignant glioma patients with high TGF-β signaling compared with glioma patients with low TGF-β signaling activity (Bruna et al, 2007). All these features make TGF-β a promising target molecule for biological treatment approaches for GBM (Wick et al, 2006). Phase I/II-studies with the TGF-β2-specific antisense oligodeoxynucleotide AP12009 in malignant glioma showed promising results (Hau et al, 2007). Another approach to target TGF-β is with monoclonal antibodies, such as GC1008. GC1008 is a fully human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGF-β (i.e., 1, 2, and 3). For therapeutic success, it may be essential for GC1008 to reach the target site, in this case located in the brain. Our own data with 89Zr-bevacizumab, which is also an IgG, showed that the VEGF directed antibody bevacizumab penetrates the brain and is localized in brain metastases. We therefore expect GC1008 to reach the malignant glioma as well. In order to initiate clinical trials with TGF-β antibody in these patients it would clearly be of great help to prove that the drug arrives at the tumor site. 89Zr-GC1008 PET imaging will allow us to prove this. In addition, PET imaging allows quantification of the amount of GC1008 reaching the malignant glioma. A phase II study with GC1008 in patients with relapsed malignant gliomas will be initiated as currently, there is no standard treatment available for these patients.

Study objectives:

Part 1: Feasibility of 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma to assess if GC1008 penetrates into the brain tumor and to quantify its uptake.