With the improved success of therapies for systemic malignancies, the craniospinal axis has become an increasingly more common sanctuary site for many human cancers resulting in an increase in the incidence of intracerebral and leptomeningeal (LM) disease causing devastating morbidity and frequent mortality. Primary central nervous system (CNS) and LM tumors are often incurable despite aggressive dose-intensive chemotherapy and radiotherapy. Treatment failures are largely due to the limitations posed by the blood brain barrier and the normal brain tolerance to these therapies. 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 the investigator employed the intrathecal radiolabeled monoclonal antibody 3F8 targeting tumor-associated antigen GD2 in healthy non-human primates whose GD2 expression in the CNS is identical to that in humans. They demonstrated that IT (131)I-3F8 can deliver a high dose of radiation to the cerebrospinal fluid with tolerable side effects. In a pilot study, patients diagnosed with GD2-positive LM tumors were imaged with intraventricular (131)I-3F8 to obtain dosimetry before RIT. Calculated radiation dose to the cerebrospinal fluid (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. This represents the first study of intraventricular (131)I-radiolabeled antibodies targeting GD2 in patients with LM cancer. Given the selective tumor uptake, tumor dose is expected to be 5 to-10 fold the cerebral spinal fluid dose for GD2-rich malignancies. The investigators propose to extend these studies to define the toxicity, efficacy, pharmacokinetics and dosimetry of intraventricular (131)I-3F8 in the detection and treatment of GD2 positive LM cancers.
|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|