? With the improved success of therapies for systemic malignancies, the crainospinal axis has become an increasingly more common sanctuary site for many human cancers, resulting in an increase in the incidence of intracerebral and LM disease causing devastating morbidity and frequent mortality. Primary 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 investigators employed IT radiolabeled murine 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-l-3F8 can deliver a high dose of radiation (up to 82 Gy) to the cerebrospinal fluid with tolerable side effects. In a recently completed Phase 1 study, patients diagnosed with GD2-positive LM tumors were imaged with intraventricular 131-l-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. Dosimetry to cerebrospinal fluid and bone marrow appeared favorable for therapeutic purposes. Clinical, radiographic and cytologic responses were observed. The investigators now propose to define responses to this therapy in a Phase 2 single-arm open-label study. Patients will receive IT 131-l-3F8 treatment cycle (10 mCi/cycle) approximately monthly for a total of 4 cycles (total 40 mCi). Response will be assessed by neurologic examination, radiographic imaging and CSF cytology analysis.
Other aims will be met by monitoring patients clinically and biochemically for cumulative toxicity and by serum assessment of human-anti-mouse antibody response. This study will be the basis for other regional therapies using radiolabeled-antibodies targeting tumor associated antigens for other CNS malignancies. ? ?
| 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 |
