The severe morbidity and mortality caused by tumors metastatic to the leptomeninges is a major impediment to curing pediatric cancers including leukemias and solid tumors. We postulate that leptomeningeal space represents a major conduit for metastatic spread to the entire CNS. Therapeutic strategy directed at tumor cells in this space is inadequately explored, and the natural history of this complication is painful and uniformly lethal. Treatments aimed at eradicating microscopic deposits in the CNS are needed to treat this sanctuary site. Regional therapy with radiolabeled monoclonal antibodies (RIT) offers the advantage of maximizing concentration to tumor sites while reducing systemic toxicities. To test this principle, we employed the intrathecal (IT) radiolabeled murine monoclonal antibody 3F8 targeting tumor associated antigen GD2 to patients diagnosed with GD2-positive LM tumors were imaged with intraventricular 131-I-3F8 to obtain dosimetry before RlT. Calculated radiation dose to the CSF was up to 57 cGy/mCi, and to blood and other organs less than 2 cGy/mCi. Acute side effects were self-limited. 131-I-3F8 successfully detected LM disease. Dosimetry to cerebrospinal fluid and bone marrow appeared favorable for therapeutic purposes. In similar studies, we have developed a murine monoclonal antibody, 8H9, that recognizes a unique 58 kD glycoprotein antigen homogeneously distributed on the cell membrane of a broad spectrum of pediatric and adult solid tumors of neuroectodermal, mesenchymal and epithelial origin. In contrast to 3F8, normal tissue expression is restricted. 8H9 can be radiolabeled with I-125 and I-131 and retains its immunoreactive properties. It has the potential to specifically target solid tumors in humans allowing the delivery of radiation or other therapeutic agents with limited toxic effects on normal tissues. Since the antibody 8H9 reacts with many solid tumors in the adult population (including melanoma, breast cancer, brain tumors) it may have broader clinical utility. Intravenous and intraventricular 131-I-8H9 are being studied in novel clinical trials for patients with 8H9-expressing malignancies. Thus far, a high dose to the CSF has been delivered (39-220 cGy/mCi) with a significantly reduced dose to the blood (0.5-5.5 cGy/mCi) in patients receiving IT 131-I-8H9. Limited acute toxicity has been observed to date. This study will explore the IT application of 131-I-8H9 in patients with 8H9-expressing CNS malignancies on a phase I study, and be the basis for other regional therapies using radiolabeled antibodies targeting additional tumor associated antigens.
| Kramer, Kim; Kushner, Brian H; Modak, Shakeel et al. (2010) Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol 97:409-18 |
