Using Immune Cells for Transport of Therapeutics to Brain Tumors

                            http://www.mathewsopenaccess.com/cancer-science-current-issue.html

Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Currently, no curative therapies are available for GMB. Merely palliative treatments only prolong survival 12-14 months after diagnosis. One of the greatest obstacles to GBM therapy is the blood-brain barrier (BBB) that severely limits the brain penetration of more than 95% of all promising therapeutics. However, classes of immune cells (monocytes and macrophages), as well as stem cells have an extraordinary ability to cross the BBB due to enhanced margination and extravasation. These immune cells can be genetically modified to express diagnostic markers or secreted therapeutic molecules directed against death receptors on GBM cells. Furthermore, exosomes released from immune cells can be loaded with cytotoxic agents and utilized for the drug transport across the BBB. Capitalizing on the powerful tumor-focused homing of immune cells, this approach directly addresses the critical deficiencies in traversing the BBB and tumor-specific accumulation plaguing current anti-GBM therapies. Noteworthy, beside the treatment of primary brain tumor, eradication of brain metastasis may also be addressed by means of cells-mediated drug delivery. In this review, we discuss new drug delivery systems that utilize living cells for drug carriage to the brain tumors.

The use of living cells for active targeted drug delivery to brain tumors is a new concept that has a potential to open different therapeutic avenues within the central nervous system (CNS). The current standard of care for glioblastoma multiforme (GBM) is surgery and chemo-radiation therapy, yet this approach is grossly inadequate and patient mortality remains high universally. Cell-based therapy is an innovative approach that is not only a departure from traditional systemic or forced-infusion drug delivery, but also alters kinetics to provide prolonged and focused drug delivery to tumors. Using inflammatory response cells enables targeted drug transport and prolonged circulation times, along with reductions in cell and tissue toxicities. In addition, these cells are capable of cell-to-cell transmission of their cargo that improves therapeutic outcomes. Noteworthy, a proper differentiation of drug carriers into particular subtypes may further boost the therapeutic efficiency of cell-based drug formulations.

To achieve anti-tumor efficacy, immune cells should be loaded with therapeutics. However, drug loading in cell-carriers is often low, drugs must be efficiently unloaded at the tumor, and drugs must not affect the survival or migration of the carrier. This has created a bottleneck for cell-based cancer therapy. To this end, protein-based therapies that are the ideal drug for cell-mediate delivery to GBM have been recently developed. Thus cell-based carriers “armed” with the targeted anti-cancer proteins could represent a novel and highly effective therapy for GBM. Another approach is based on using exosomes, released from immune cells. These nano-sized naturally occurred extracellular vesicles can be loaded with cytotoxic drugs and then used for drug transport to the brain tumors. Reflective of their origin, these nanocarriers can cross the blood-brain barrier (BBB) and target cancer cells in the brain. Such systems for drug carriage and targeted release represent a novel strategy that can be applied to a spectrum of human disorders.