Pre-Targeted Locoregional Radioimmunotherapy with ⁹⁰Y-biotin in Glioma Patients: Phase I Study and Preliminary Therapeutic Results

Abstract

The aim of this study was to determine the maximum-tolerated dose, of a pre-targeting three-step (3-S) method employing 90Y-biotin in the locoregional radioimmunotherapy (RIT) of recurrent high grade glioma, and to investigate the antitumor efficacy of this new treatment. Twenty-four patients with recurrent glioma underwent second surgical debulking and implantation of a catheter into the surgical resection cavity (SRC), in order to introduce the radioimmunotherapeutic agents [biotinylated monoclonal antibody (MoAb), avidin and 90Y-biotin]. Eight patients with anaplastic astrocytoma (AA) and 16 patients with glioblastoma (GBM) were injected with biotinylated anti-tenascin MoAb (2 mg), then with avidin (10 mg; 24 h later) and finally 90Y-biotin (18 h later). Each patient received two of these treatments 8-10 weeks apart. The injected activity ranged from 0.555 to 1.110 GBq (15-30 mCi). Dosage was escalated by 0.185 GBq (5 mCi) in four consecutive groups. The treatment was well tolerated without acute side effects up to 0.740 GBq (20 mCi). The maximum tolerated activity was 1.110 GBq (30 mCi) limited by neurological toxicity. None of the patients developed hematologic toxicity. In three patients infection occurred around the catheter. The average absorbed dose to the normal brain was minimal compared with that received at the SRC interface. At first control (after 2 months), partial (PR) and minor (MR) responses were observed in three GBM (1 PR; 2 MR) and three AA patients (1 PR; 2 MR) with an overall objective response rate of 25%. Stable disease (SD) was achieved in seven GBM and five AA patients (50%). There was disease progression in six GBM patients (25%), but in none of the AA patients. At the dosage of 0.7-0.9 GBq per cycle, locoregional 3-S-RIT was safe and produced an objective response in 25% of patients. Based on these encouraging results, phase II studies employing 3-S-RIT soon after first debulking are justified.

Novel antibodies as anticancer agents

“…This conjugate demonstrated promising results with a sensitivity of 76.5% and a specificity of 100%. In phase I trials, Paganelli et al (2001) have used a three step pretargeting regimen by a locoregional administration of biotinylated antitenascin mAb to recurrent high-grade glioma patients, subsequent administration of avidin and finally administration of Novel antibodies as anti-cancer agents I Zafir-Lavie et al 90 Y-biotin. The overall response rate was 25%, and stable disease was achieved in 50% of the patients.…”

“…The overall response rate was 25%, and stable disease was achieved in 50% of the patients. Phase II trials have shown great efficacy of the radioimmunoconjugate as adjuvant treatment in prolonging patient's lives (Paganelli et al, 2001;Grana et al, 2002;Smith-Jones and Solit, 2004). RIT has proven efficient and most marked in hematologic neoplasms.…”

Novel antitenascin antibody with increased tumour localisation for Pretargeted Antibody-Guided RadioImmunoTherapy (PAGRIT)

“…A three-step Pretargeted Antibody-Guided RadioImmunoTherapy (PAGRIT) approach for systemic and locoregional treatment of brain tumours was previously shown to be safe and to produce clinical benefits to patients Paganelli et al, 1999Paganelli et al, , 2001Grana et al, 2002).…”

“…The role of the biotinylated antitenascin antibody is to display biotins at the tumour site in order to mediate subsequent streptavidin and 90 Y-biotin accumulations. The monoclonal antitenascin antibodies BC4 and BC2 described by Siri et al (1991) and Balza et al (1993) have been previously used, with success, in both systemic and topical, pretargeted or direct therapeutic settings in patients with brain tumours (Riva et al, 1997;Paganelli et al, 1999Paganelli et al, , 2001Grana et al, 2002). However, both BC2 and BC4 hybridoma clones were found unsuitable for process development because of the production of an additional, nonfunctional light chain (most likely of parental myeloma origin) whose increased level of expression in the scaled-up cultivation prevented a large-scale antibody purification (Vola et al (1993) and results from our laboratories).…”

Targeted radiotherapy of brain tumours

“…The first trial with this pretargeting approach was performed in patients with recurrent glioma and the three reagents were administered via a catheter placed into the surgical resection cavity (Paganelli et al, 2001). In all, 16 patients with glioblastoma and eight with anaplastic astrocytoma were treated with two cycles administered 8 -10 weeks apart.…”