Editors' ChoiceCancer

A trojan horse for treatment of brain tumors

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Science Translational Medicine  11 Sep 2019:
Vol. 11, Issue 509, eaaz0310
DOI: 10.1126/scitranslmed.aaz0310

Abstract

Encapsulation and molecular targeting of therapeutic antibodies enhance CNS uptake and treatment efficacy in brain metastases.

Brain metastases are the most common cause of intracranial neoplasms. Unfortunately, 20 to 45% of cancer patients will be diagnosed with brain metastases in their lifetime. Brain metastases are responsible for decline in neurological function, reduction in overall quality of life, and mortality from recurrent or untreatable lesions. Because the brain is structurally and functionally isolated from the rest of the body by an intricate blood-brain barrier (BBB), it takes longer for tumor cells to successfully invade the central nervous system (CNS), as compared with other organs. Improved control of extracranial systemic disease and the limited ability of current therapeutics to cross the BBB may contribute to the rise in the incidence of brain metastases, as tumor cells seek refuge in the brain.

As such, a major hurdle to the treatment of CNS metastases is the BBB, which serves as a formidable barrier to protect the brain. Cancer therapies based on monoclonal antibodies are widely successful yet have limited efficacy for brain metastases, because only small amounts of the drugs reach the tumor site. Now, Wen et al. have devised a two-step Trojan horse to allow for better brain penetration of monoclonal antibody rituximab, which is used to treat patients for non-Hodgkin lymphoma with CNS metastases. First, the authors nano-encapsulated rituximab within a polymer layer that allowed for enhanced BBB penetration, increasing the CNS concentrations of the antibody by approximately tenfold with respect to naked rituximab. Second, they coated the nano-capsules with the ligand for CXCR5, a receptor often found on non-Hodgkin lymphoma. Treatment with this encapsulated rituximab Trojan horse in a murine xenograft model, decreased CXCR5-expressing brain metastases and eliminated lymphoma in a xenografted humanized bone marrow–liver–thymus mouse model.

Although these findings indicate that we can modify current therapies to increase their uptake into the sanctuary neural niche for brain metastases, they also raise several biological questions. Additional pharmacokinetics studies need to be conducted to assess whether these drugs can also cross the blood-tumor barrier, which is different from the conventional BBB and has varying degrees of leakiness. It also remains to be determined whether this two-step Trojan horse will also be able to target brain metastases from nonhematological cancers or primary brain tumors. Nevertheless, this two-step Trojan horse of encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of intracranial tumors.

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