Outwitting the Blood-Brain Barrier

November 15, 2016

The blood-brain barrier and the blood-cerebrospinal fluid barrier are major physical impediments to therapeutics targeting central nervous system neoplasms. We review this topic from the perspective of a group whose focus is on the neurovascular unit.

The blood-brain barrier and the blood-cerebrospinal fluid barrier are major physical impediments to therapeutics targeting central nervous system (CNS) neoplasms. We review this topic from the perspective of a group whose focus is on the neurovascular unit (NVU); our group considers the three-dimensional architecture of brain vasculature. In addition to the endothelial tight junctions of the cerebrovasculature, the NVU comprises astrocytic foot processes, pericytes, microglia, basement membranes, neurons, and perivascular (Virchow-Robin) spaces. As eloquently described by Lockman et al,[1] tumors can co-opt existing brain vasculature (as well as induce angiogenesis), and the NVU in these tumor-associated vessels is structurally and functionally heterogeneous. The blood-brain barrier is neither permanently open nor permanently closed; permeability is inconsistent and can vary substantially among patients, between different regions of tumor, and between different metastases within a single patient.

In this issue of ONCOLOGY, Naidoo et al outline a variety of approaches to optimizing the delivery of antineoplastic agents to the brain.[2] However, the authors' enthusiasm for most of the options described seems to be limited. Our view is more optimistic about methods such as osmotic blood-brain barrier disruption (BBBD), which has the potential to significantly improve the treatment of CNS neoplasms. Intra-arterial infusion of hyperosmotic mannitol reversibly opens the blood-brain barrier by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain by 10- to 100-fold. Preclinical studies have optimized this technique, and multiple clinical trials have demonstrated its safety and efficacy,[3] with some reporting cohort survival rates that surpass those reported in the literature.[4] The question of potential adverse effects of BBBD chemotherapy has been investigated extensively by our group. Prospective evaluation of survivors of primary CNS lymphoma who were treated with BBBD chemotherapy showed stable or improved cognitive status at a median follow-up of 12 years after diagnosis.[5] This was the first study to evaluate cognition and neuroimaging with such lengthy follow-up in patients with this rare cancer.

Naidoo et al raise important issues regarding BBBD invasiveness, toxicity, expense, and the requirement for general anesthesia.[2] At Oregon Health & Science University, we have performed intra-arterial chemotherapy delivery with or without BBBD more than 7,000 times. The procedure confers excellent long-term survival (up to 30 years) while maintaining patient cognitive function and causing minimal serious toxicity. BBBD is invasive, but it compares favorably to autologous stem cell transplant, which is associated with a 6% to 10% rate of treatment- related mortality. In contrast, the rate of treatment-related mortality with BBBD is less than 1%. While it is true that BBBD opens the blood-brain barrier only in brain regions supplied by the catheterized artery, with right or left carotid or vertebral artery infusion, this space encompasses the entire hemisphere. Because highly infiltrative brain diseases contain neoplastic cells that are often centimeters away from the enhancing tumor mass, it is essential to open the blood-brain barrier over wide brain regions. Furthermore, this technique can be safely repeated multiple times, allowing us to target different regions of brain and deliver multiple cycles of chemotherapy over the course of treatment.

Inflammatory processes within and around brain tumors adversely affect the integrity of the blood-brain barrier. Heterogeneous blood-brain barrier integrity is exemplified by MRI of brain tumors with ferumoxytol iron oxide nanoparticles. In brain tumor patients, radiographic worsening after radiation therapy may be caused by true tumor progression or may reflect treatment-induced inflammatory changes that cause increased permeability of the blood-brain barrier-a phenomenon termed pseudoprogression (see Figure, part A). In contrast to pseudoresponse, wherein tumor growth is masked behind a "normalized" blood-brain barrier following antiangiogenic treatment, patients with pseudoprogression stabilize spontaneously and demonstrate increased survival (with median survival of 13 months without pseudoprogression and 36 months with pseudoprogression; see Figure, part B).(6,7) We have shown that the MRI contrast agent ferumoxytol, which is approved by the US Food and Drug Administration for iron replacement therapy, provides clinical guidance in differentiating true tumor progression from pseudoprogression.[7-9] Because ferumoxytol is a blood pool agent, it can be used for vascular imaging early after injection. Due to its long plasma half-life (14 to 20 hours), this agent leaks slowly in regions of damaged blood-brain barrier. As a result, ferumoxytol is able to improve the consistency of measurements of relative cerebral blood volume compared with gadolinium-based contrast agents, and precludes the technical and mathematical manipulations necessary to measure vascular changes on MRI.[10] At later time points (24 hours), it is taken up by inflammatory cells, including macrophages, microglia, dendritic cells, and B cells. Thus, ferumoxytol can provide a biomarker of inflammatory cells, as well as lymphoma cells, but not other types of tumor cells.

Together, measurements of relative cerebral blood volume delineating actively growing tumor and delayed imaging of tumor inflammation can improve assessment of tumor growth and response to therapy, which is especially important in this era of novel immunotherapeutics.

We concur with Naidoo et al that novel immunotherapy techniques are creating exciting new opportunities to enhance drug delivery to the CNS and are similarly encouraged by promising early data. In recent years, monoclonal antibodies such as rituximab have been added to the BBBD primary CNS lymphoma treatment regimens. We showed that the monoclonal antibody rituximab has excellent efficacy in preclinical models of CNS lymphoma, even with intravenous administration only.[11] This efficacy is likely a result of the 14- to 21-day half-life of rituximab, which allows leakage of therapeutic levels; indeed, when tumors recur they do so away from the initial tumor mass. Clinically, we have found that rituximab substantially improves the rates of complete response and overall survival in primary CNS lymphoma when compared with response rates achieved in its absence.[12]

In short, it is possible to manipulate the blood-brain barrier so as to have major therapeutic impact in neuro-oncology. We believe that the biggest issues to be addressed are:

• The lack of effective non-neurotoxic agents that are safe to deliver across the blood-brain barrier.

• The tremendous variability of blood-tumor barrier permeability in both primary and metastatic brain tumors, regardless of tumor size.

• The lack of a reliable, validated, and specific noninvasive biomarker for response assessment that can differentiate tumor effects from inflammation and effects of treatment.

Finally, we believe that increased understanding of how NVU components function in health and disease will be the key to advancing drug delivery efforts in the setting of brain tumors.

Financial Disclosure:The authors have no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Lockman PR, Mittapalli RK, Taskar KS, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16:5664-78.

2. Naidoo J, Panday H, Jackson S, et al. Optimizing the delivery of antineoplastic therapies to the central nervous system. Oncology (Williston Park). 2016;30:953-62.

3. Angelov L, Doolittle ND, Kraemer DF, et al. Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol. 2009;27:3503-9.

4. Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA. Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. Adv Pharmacol. 2014;71:203-43.

5. Doolittle ND, Dosa E, Fu R, et al. Preservation of cognitive function in primary CNS lymphoma survivors a median of 12 years after enhanced chemotherapy delivery. J Clin Oncol. 2013;31:4026-7.

6. Gahramanov S, Muldoon LL, Varallyay CG, et al. Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival. Radiology. 2013;266:842-52.

7. Gahramanov S, Varallyay C, Tyson RM, et al. Diagnosis of pseudoprogression using MRI perfusion in patients with glioblastoma multiforme may predict improved survival. CNS Oncol. 2014;3:389-400.

8. Gahramanov S, Raslan AM, Muldoon LL, et al. Potential for differentiation of pseudo-
progression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys. 2011;79:514-23.

9. Nasseri M, Gahramanov S, Netto JP, et al. Evaluation of pseudoprogression in patients with glioblastoma multiforme using dynamic magnetic resonance imaging with ferumoxytol calls RANO criteria into question. Neuro Oncol. 2014;16:1146-54.

10. Gahramanov S, Muldoon LL, Li X, Neuwelt EA. Improved perfusion MR imaging assessment of intracerebral tumor blood volume and antiangiogenic therapy efficacy in a rat model with ferumoxytol. Radiology. 2011;261:796-804.

11. Muldoon LL, Lewin SJ, Dosa E, et al. Imaging and therapy with rituximab anti-CD20 immunotherapy in an animal model of central nervous system lymphoma. Clin Cancer Res. 2011;17:2207-15.

12. Doolittle ND, Fu R, Muldoon LL, et al. Rituximab in combination with methotrexate-based chemotherapy with blood-brain barrier disruption in newly diagnosed primary CNS lymphoma. Hematol Oncol. 2013;31(suppl 1):poster 247. http://onlinelibrary.wiley.com/doi/10.1002/hon.2058/pdf. Accessed October 20, 2016.