The occurrence of CNS metastases of systemic cancers far exceed the number of primary malignant brain tumors. Current therapies such as radiosurgery are effective for short-term palliation of CNS metastases, however, often do not provide long-term disease control. In many cases, WBRT used to treat CNS metastases has been associated with neuro-toxicity. BBBD enables global delivery of chemotherapy to all cerebral circulations, and thus may offer a new treatment strategy for CNS metastases, administered before or after radiosurgery or WBRT. Based on the results of BBB pre-clinical studies, it is hypothesized that pre-irradiation BBBD chemotherapy may allow better drug penetration to CNS metastases in the clinical setting.
Tumor-specific mAbs can be used as anti-neoplastic agents or as delivery systems for anti-tumor therapies. A clinical protocol is under development for the use of mAb against the epidermal growth factor receptor (EGFR) in patients with breast cancer with CNS metastases. Chemotherapy will consist of monthly methotrexate and carboplatin, infused intra-arterially in conjunction with BBBD. HER-2 positive patients will receive trastuzamab (Herceptin) the evening prior to BBBD. Patient's neuropsychologic and quality of life status will be closely followed.
Translational studies have led to promising new targeted therapies such as the EGFR antagonists, used alone or as a part of combination therapy. Herstatin, a naturally occurring product of the HER-2 gene created by alternative mRNA splicing, blocks receptor dimerization and activation of EGFR . Since glioblastoma is often driven by EGFR activation or mutation, we evaluated the potential for treatment with Herstatin in a rat glioblastoma model. Herstatin blocked the growth of intracerebral glioma expressing the normal EGFR, whereas in vivo and in vitro growth of cells expressing a mutant constitutively active EGFR were resistant to Herstatin. BBBD may provide a method to optimize CNS delivery of agents such as Herstatin and even viral vectors. As Herstatin can spread to and inhibit adjacent tumor cells, it may be effective as a transgene for gene therapy of CNS tumors .
In the pre-clinical setting, we have studied the BR96 mAb which binds to a LewisY-related antigen expressed in lung, breast, ovarian, and colon cancer. The conjugate of BR96 mAb with adriamycin (BR96-DOX) is effective against a number of human carcinoma xenografts in rodents . The efficacy of immunotherapy or immunoconjugates is limited by poor penetration in solid tumors. Additionally, antibodies do not cross the BBB. We are investigating the use of radiolabeled tumor-specific antibodies against brain tumors; an approach which could be further optimized by BBBD to achieve global delivery .
mAbs against the CD20 antigen, expressed by nearly all B-cell lymphomas, show promise. As previously mentioned, we are studying rituximab administered the evening prior to BBBD chemotherapy, in patients with relapsed PCNSL. On the horizon is the use of radiolabeled anti-B-cell antibodies in the treatment of relapsed PCNSL. We are interested in exploring the use of ibritumomab tiuxetan in conjunction with BBBD in relapsed PCNSL. In addition, a study is planned to assess the safety and efficacy of intravitreal rituximab in patients with intra-ocular lymphoma. As part of the study, apoptosis will be evaluated in vitreal cells, at multiple time points after injection of rituximab. There is evidence from the intravitreal injection of another immunoglobulin that this class of therapeutic agents can be efficacious and administered intravitreally with acceptable toxicity.
Neuro-imaging techniques have become increasingly important in assessing biologic and physiologic aspects of brain tumors. The ability to image infiltrative disease and to better assess the extent of disease and actual tumor volume is critical. Our group has shown, using ultra small iron oxide particles (USPIOs), improvement in imaging tumor microvasculature and larger areas of tumor enhancement, in some cases . Delayed imaging has shown that the USPIO is taken up into tumor macrophages and reactive astrocytes, visualized histochemically . Due to the virus-like size of the USPIO, penetration of viral vectors may be monitored, when using gene therapy.
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