Optimizing the Delivery of Antineoplastic Therapies to the Central Nervous System

Despite significant advances in the treatment of systemic cancers, progress in the treatment of primary brain tumors has been quite modest. In addition, an increasing proportion of patients with systemic cancers are presenting with brain-only metastases. These observations highlight the critical role that the blood-brain barrier plays in preventing antineoplastic therapies from reaching the central nervous system in therapeutic concentrations. This review describes the anatomy of the blood-brain barrier and currently available methods to quantify the entry of therapeutic compounds into the brain. It also summarizes data from a variety of approaches designed to improve drug delivery to the central nervous system. These include: 1) directly placing drugs inside the blood-brain barrier (polymeric implants, convection-enhanced delivery, and intraventricular administration), 2) modifying systemic chemotherapy (by using high-dose methotrexate and intra-arterial drug administration), 3) temporary disruption of the blood-brain barrier (via use of intra-arterial mannitol, focused ultrasound, or pharmacologic agents), and 4) designing drugs that can pass through the blood-brain barrier. Given that lymphocytes readily traverse the blood-brain barrier, immunotherapy represents a novel approach to cancer therapy that is of particular interest to practitioners in the field of neuro-oncology. The efficacy of vaccines and immune checkpoint inhibitors is currently being actively investigated in patients with primary and metastatic brain tumors, as well as leptomeningeal carcinomatosis. The challenge of delivering effective antineoplastic therapies to the central nervous system remains a primary obstacle to improving outcomes in patients with primary and metastatic brain tumors.

Background

Clinical importance

The treatment of many solid tumors and hematologic malignancies has improved significantly in recent years. However, primary or metastatic lesions in the central nervous system (CNS) remain clinically challenging, partly because systemically administered anticancer therapies have poor penetration through the blood-brain barrier. Even temozolomide, which is known to cross the blood-brain barrier and improve survival in patients with glioblastoma, has concentrations in the brain that are only 20% of those in the blood.[1]

The incidence of metastatic disease to the CNS is approximately 10 times greater than that of primary brain cancers. It is estimated that 20% to 40% of patients with solid tumors will eventually develop parenchymal brain or leptomeningeal metastases.[2] These patients have a poor prognosis and limited treatment options, and they are commonly excluded from clinical trials. Recent improvements in systemic therapy for solid tumors have been accompanied by an increasing number of patients who experience isolated disease progression in the CNS. These challenges highlight the importance of understanding the blood-brain barrier and how to improve the delivery of drugs to the CNS.

Structure and Function of the Blood-Brain Barrier

The blood-brain barrier is a physiologic entity comprising astrocytes, endothelial cells, pericytes, and associated proteins that govern the entry of molecules into the CNS.[3] This barrier exists along all brain capillaries and features tight junctions not present within the normal circulation. These tight junctions provide highly selective separation of circulating blood from interstitial fluid in the CNS. The endothelial cells of the brain and connecting tight junctions restrict the diffusion of microscopic objects (such as bacteria) and large molecules, while allowing the passive diffusion of water, some gases, and lipid-soluble molecules. The cells of the blood-brain barrier also selectively transport molecules crucial to neural function, such as glucose and amino acids, while preventing the entry of potential neurotoxins via an active transport mechanism mediated by P-glycoprotein.[3,4] In general, the blood-brain barrier impairs entry of hydrophilic and large (molecular weight [MW] > 400 Da) agents into the CNS. Brain imaging by CT and MRI relies on alterations in the integrity of the blood-brain barrier to localize brain tumors. Capillaries within these cancers often have a disrupted blood-brain barrier, which allows water-soluble contrast agents to enter brain parenchyma in the affected areas, allowing ready visualization of the tumors.[5] This loss of integrity also allows albumin (MW, 60 kDa) to pass from the circulating blood into the brain parenchyma, where it osmotically draws in water, resulting in brain edema, mass effect, and neurologic compromise. Additionally, the integrity of the blood-brain barrier can be modified by therapies commonly prescribed by oncologists, such as radiation, which increases permeability of the barrier, and dexamethasone or vascular endothelial growth factor inhibitors, which restore its integrity.[6] Tumor-associated disruption may also permit certain drugs that would typically be excluded from CNS penetration to enter contrast-enhancing regions of brain tumors.[6]

Predicting Which Drugs Will Pass Through the Blood-Brain Barrier

Antineoplastic agents administered systemically to treat CNS malignancies must reach cancer cells in the brain in order to be effective. For this to occur, the administered drugs must leave the blood and traverse both the blood-brain barrier and extracellular matrix to reach malignant glial cells.[4] This process is often complicated by interstitial pressure gradients and efflux transporters. It has been estimated that the blood-brain barrier blocks nearly all large-molecule neurotherapeutics and more than 98% of all small molecules from CNS access.[7] The most common factors used to predict penetration of the blood-brain barrier include:

1) Lipid solubility as measured by a log P (ratio of solute concentrations in octanol relative to water) between 1.5 and 2.7 and/or a log D (ratio of solute concentrations in octanol relative to water at a specified pH) between 1 and 3 at physiologic pH.

2) MW < 400 Da.

3) Charge (a small molecular polar surface area such as < 60-70 Ų).

4) Few nitrogen and oxygen atoms (< 8–10 is optimal).

5) Physical size < 11 nm.[8]

Even in contrast-enhancing regions of human brain tumors, where one might expect easy entry of chemotherapy, large variations in drug concentrations within the brain tumor compared with concentrations in blood have been noted; these differences appear to be related to lipid solubility and MW.[8]

Quantifying the Entry of Drugs Into the CNS

A variety of approaches are available to estimate the concentrations of systemically administered chemotherapy that reach brain tumor tissue in humans (Table 1). Although cerebrospinal fluid (CSF) has been used to estimate drug penetration into the CNS, the concentrations of drug reaching the CSF as opposed to brain parenchyma or tumor tissue are significantly different, making CSF an unreliable surrogate for brain penetration.[3] More reliable approaches utilize direct measurements of drug concentrations within brain parenchyma and tumor tissue. These can be obtained by placing microdialysis catheters in residual brain tumor tissue at the time of surgery, followed by oral or intravenous drug administration and measurement of pharmacokinetic profiles of the drug over time, in the extracellular fluid in the brain or tumor, and in blood.[9] This approach has provided very informative data on the penetration of high-dose methotrexate and temozolomide in patients with brain tumors.[1,2,10] Alternatively, the agent of interest can be administered prior to a clinically indicated surgical debulking of the tumor, and drug concentrations can then be measured in excess tumor tissue. This approach is being used with increasing frequency before drug efficacy studies are considered. Imaging modalities can also be used to estimate drug penetration into the CNS. Some agents can be radiolabeled with an isotope that can be visualized with single-photon emission CT or positron emission tomography imaging, while others may be amenable to quantitation using MR spectroscopy. These noninvasive techniques can provide serial data from both contrast-enhancing and nonenhancing regions of the brain.

Approaches for Improving the Delivery of Therapeutic Agents to the CNS

A variety of approaches for improving the delivery of therapeutic concentrations of antineoplastic therapies to the brain have been explored. Those studied most extensively are outlined in Table 2 and described below.

Direct placement of drugs inside the blood-brain barrier

For decades, investigators have attempted to circumvent the blood-brain barrier by placing therapeutic agents directly within the CNS. The techniques explored include: 1) administration of agents into the CSF, 2) direct injection into brain parenchyma, 3) convection-enhanced delivery (CED) using a surgically implanted catheter attached to an external pump, and 4) implantation of biodegradable chemotherapy-laden polymeric wafers at the time of surgery. Experiences with these approaches are briefly summarized here.

Direct administration into the CSF. Early studies of intrathecal chemotherapy were prompted by isolated leptomeningeal recurrences in patients with acute lymphocytic leukemia. Treatment was initially provided via a lumbar puncture, but evolved into a more convenient and reliable method in which the drug was administered through a ventricular catheter attached to a subcutaneous reservoir (Ommaya reservoir).[11] While humans have approximately 150 mL of CSF within the CNS at any time, approximately 550 mL of CSF is produced daily.[12] As a result, therapeutic agents injected into the CSF are rapidly cleared by normal CSF flow and are ultimately delivered to the venous circulation via the arachnoid granulations.[12] Autoradiography studies have been performed in animals to determine the penetration of intraventricularly administered drugs into brain parenchyma.[13] These have demonstrated that only 1% to 2% of the CSF drug concentration is achieved at a distance of 2 mm from the ependymal surface. As a result, although this route of delivery is reasonable in patients with leptomeningeal disease, it is highly unlikely to enable therapeutic drug concentrations to reach intraparenchymal neoplasms.

Single injections into brain parenchyma. A variety of chemotherapeutic agents or viral products have been administered directly into brain parenchyma.[2,14] This is commonly accomplished using intraoperative injections into the wall of a surgically created tumor resection cavity or by direct stereotactic injection of therapy into an existing tumor mass. Studies examining the distribution of the agents administered in this manner suggest that lipid-soluble chemotherapies have low retention times within the tumor or normal brain, since they are able to cross the blood-brain barrier in either direction and are rapidly detected in the venous circulation. Larger compounds, such as viral products, tend to remain where they were injected, leaving large portions of residual tumor tissue untreated.[14] In addition, the pressure required to inject the therapeutic agent into brain parenchyma frequently results in reflux of drug along the needle track where it enters the CSF and is cleared by normal CSF flow. Therefore, this approach is now largely limited to phase I and II studies of injections of experimental agents designed to create a local immune response, rather than attempts to treat the entire tumor volume.

Convection-enhanced delivery. CED is a natural extension of efforts to directly inject chemotherapy into CNS tumors and adjacent brain tissue. This procedure involves the stereotactic placement of a specially designed catheter that is radiologically guided to the target site at the time of surgery. The catheter is then attached to an external pump, and the agent of choice is administered by a slow continuous infusion over several days. This approach minimizes reflux and improves drug distribution through the brain interstitium as a result of low administration pressures and the use of specialized catheters.[15] It also permits administration of both large- and small-molecular-weight compounds, and results in high local concentrations with low systemic exposures, minimizing systemic toxicity. It is possible to estimate the intracranial distribution of the infused drug by adding either a radioactive tracer or a contrast agent to the fluid being infused from the pump; these can be followed serially using neuroimaging modalities.[16] CED has been used in both preclinical and clinical settings to deliver high concentrations of therapeutic agents to the brain. A phase II study of a transferrin receptor ligand–targeted diphtheria toxin conjugate (Tf-CRM107) administered via CED to patients with recurrent glioblastomas resulted in an objective response rate of 35%.[17] A phase III study was conducted comparing the CED infusion of chimeric recombinant human interleukin-13 plus pseudomonas exotoxin vs local chemotherapy delivered by carmustine wafers (bischloroethylnitrosourea, also known as BCNU).[18] Unfortunately, neither of these approaches generated statistically significant survival gains. More recently, a phase I study of topotecan administered by CED reported encouraging survival data in carefully selected patients with recurrent high-grade gliomas.[19] Currently, however, there are no clinically approved indications for use of CED delivery of topotecan in this setting. Drawbacks of this technique include its invasiveness; expense; use that is limited to patients with localized tumors in favorable locations; uneven and/or unpredictable drug distribution; and the potential for local neurotoxicity at the region of the catheter tip, where drug concentrations are the highest. Despite these challenges, further investigation and refinement of CED are warranted in settings with a dedicated team experienced in its use.

Polymeric implants. Another approach to administering therapeutic agents directly into brain parenchyma involves placing chemotherapy-containing biodegradable polymers into the surgical cavity after removal of a primary or metastatic brain tumor. Although polymers containing different drugs have been studied preclinically, only polymers containing BCNU are approved by the US Food and Drug Administration (FDA) for patients with newly diagnosed and recurrent high-grade gliomas.[20] The administration of BCNU via thin wafers implanted in the brain provides high local concentrations of drug, without the dose-limiting myelosuppression associated with systemic administration.[21] Phase III studies were first reported in 1995 in 222 patients with recurrent malignant gliomas who were randomized to receive either BCNU-loaded or placebo polymers.[21] The BCNU polymers provided a significant survival advantage, which led to their approval by the FDA in 1996. A subsequent placebo-controlled, double-blind study in patients with newly diagnosed high-grade gliomas randomized to receive radiation with either placebo or BCNU-loaded polymers also demonstrated a survival advantage with BCNU in newly diagnosed patients, leading to FDA approval in this setting.[22] Although treatment with BCNU wafers improves outcomes in patients with newly diagnosed and recurrent high-grade gliomas, the clinical impact of this approach on the survival of the majority of patients suitable for this treatment modality is modest. These wafers are best placed in patients with localized tumors that are to be managed by a gross total resection, and in situations where the surgery is unlikely to expose the ventricles. Further, although there is an effect on median survival, the use of BCNU wafers does not improve 1- or 2-year overall survival, unlike results seen with temozolomide. BCNU is also a highly lipid-soluble compound, which may limit its retention and distribution within the CNS. Nevertheless, experience with this polymeric delivery system clearly documents the therapeutic potential of local drug delivery in patients with primary brain tumors.

Modifications in systemic chemotherapy

Another approach to improving CNS drug concentrations is to increase the systemic concentrations of chemotherapeutic agents in the blood supplying the CNS. This can be achieved by using high doses of systemic chemotherapy or administering chemotherapy through a catheter placed in the artery that supplies blood to the brain. Both of these approaches have been used extensively in patients with primary brain tumors.

High-dose systemic chemotherapy. High-dose chemotherapy, alone or followed by autologous bone marrow rescue, has been studied in adults and children with primary brain tumors. The clinical impact of this technique has been limited by poor chemoresponsiveness of CNS tumors, low intracranial drug levels, and limited ability to repeatedly administer therapy. However, it is clear that in patients with primary CNS lymphomas, treatment with high-dose methotrexate is responsible for markedly improved survival outcomes. Standard treatment with whole-brain irradiation provides a median survival time of about 1 year, but it is associated with long-term neurotoxicities and does not improve survival. However, the median survival of patients treated only with high-dose methotrexate is approximately 5 years, documenting the importance of improved drug delivery.

Intra-arterial chemotherapy. An alternate way to expose the brain to higher concentrations of systemically administered chemotherapy is to deliver drugs intra-arterially. This approach provides high drug concentrations during initial passage of chemotherapy through the brain area supplied by the infused vessel, but thereafter the drug levels are equivalent to those achieved by an intravenous injection. This technique has been studied extensively in humans with primary brain tumors.[23] A phase III trial in the 1990s evaluated intra-arterial vs intravenous BCNU in more than 300 patients with glioma.[24] A more recent study comparing these techniques demonstrated that the use of intra-arterial BCNU in patients with glioblastoma conferred no survival advantage, and was associated with reduced survival in patients with anaplastic astrocytoma.[25] In addition, intra-arterial BCNU has been associated with ipsilateral visual loss and leukoencephalopathy in infused areas of the brain.[26] Given the risks and expense of placing intra-arterial catheters, the lack of convincing survival differences, and the fact that these tumors are often not confined to the distribution of one arterial vessel, this approach is not being widely pursued.

Temporary disruption of the blood-brain barrier. Another approach aimed at improving drug delivery to the CNS is to employ methods that will transiently disrupt the blood-brain barrier at the time of systemic administration of the treatment drug. Three very different strategies for achieving this are now under clinical investigation. These include the administration of intra-arterial mannitol, the application of focused ultrasound, and the use of various vasoactive peptides, as detailed below.

• Intra-arterial mannitol. The administration of intra-arterial mannitol into the carotid or vertebral arteries results in an osmotic contraction of endothelial cells, which opens paracellular spaces for the passage of drug. This was first reported in 1972 when Rapoport demonstrated that this produced extensive extravasation of the Evans blue-albumin complex (MW, 60 kD) into brain parenchyma.[27] This disruption lasts for 30 to 120 minutes, during which time viral vectors, recombinant proteins, nanoparticles, and monoclonal antibodies can be transported across a previously intact blood-brain barrier. Mannitol has been administered intra-arterially with a wide variety of systemic agents, including bevacizumab, etoposide, melphalan, cetuximab, and temozolomide; significant neurotoxicity has been noted with temozolomide therapy.[28] Intra-arterial mannitol in combination with methotrexate has resulted in improved survival outcomes in patients with primary CNS lymphomas.[29] It has also been shown to result in clinical responses in patients with primitive neuroectodermal tumors, germ cell tumors, and brain metastases from solid tumors.[29] Although this approach has merit, it has several drawbacks, including invasiveness, toxicity, expense, the need for general anesthesia, and disruption of the blood-brain barrier only in regions of the brain supplied by the catheterized artery.

• Focused ultrasound. MRI-guided focused ultrasound can transiently disrupt the integrity of the blood-brain barrier, especially if it is used in combination with intravenously administered microbubbles. These potentiate reversible thermal and mechanical injury, which widens the tight junctions between endothelial cells and allows systemically administered agents to enter the brain parenchyma.[30-32] Focused ultrasound has been used to increase the delivery of various chemotherapeutic drugs, such as doxorubicin, methotrexate, trastuzumab, temozolomide, and BCNU, to the brain in animal models.[33-35] The major advantages of this technique are that it is relatively noninvasive, safe, and transient, with endothelium apparently recovering completely even with repeated cycles. However, the area targeted is usually small, not all locations within the brain are equally accessible to this therapeutic approach, and there are currently no human efficacy data to support its use.

• Coadministration of vasoactive peptides. Another approach to transiently improving blood-brain barrier permeability to large and/or hydrophilic chemotherapy is the coadministration of vasoactive peptides.[27,36] Older studies demonstrated that intra-arterial administration of leukotriene C4 resulted in selective opening of the blood-brain barrier in rat glioma models.[36,37] While effective in increasing blood-brain barrier permeability during delivery, the morbidity associated with intra-arterial drug administration remains a challenge. Regadenoson, an FDA-approved intravenously administered adenosine receptor agonist, has also been shown to increase the permeability of the blood-brain barrier to dextran 70 kDa and temozolomide (MW, 194 Da) in rat models.[38] Additional studies with this compound are warranted, since the doses used in patients to date are only those that are FDA approved for chemical cardiac stress tests. The primary advantage of this approach is that these agents could be administered on an outpatient basis with the desired chemotherapy, in an effort to prevent isolated brain recurrences from systemic cancers.

Choosing or designing agents specifically to cross the blood-brain barrier. There have been extensive efforts to choose or design therapeutic agents that penetrate the blood-brain barrier, with the goal of treating a wide variety of neurologic, psychiatric, infectious, and oncologic disorders. Several strategies are highlighted in Table 3. Despite intriguing results in preclinical models, these approaches have not resulted in FDA approvals for patients with primary or metastatic brain tumors. Select agents with properties that promote penetration of the blood-brain barrier include nitrosoureas (CCNU [lomustine] and BCNU) and temozolomide.

The following approaches to circumventing the blood-brain barrier are under investigation:

• Surround hydrophilic molecules in liposomes. Unfortunately, these liposomes are rapidly cleared from the systemic circulation by the reticuloendothelial system such that high brain concentrations do ot result. A modification of this approach would be to conjugate drug-carrying liposomes to a vector for drug delivery across the blood-brain barrier.

• Synthesize prodrugs with favorable blood-brain barrier penetration properties that are converted to the active drug within the CNS. This has been complicated by reduced retention in brain tissue and enhanced uptake in other organs.

• Design chemical delivery systems using a lipid-soluble compound that, once it enters the brain, is converted to a lipid-insoluble compound to enhance retention in the brain.

• Use existing transport systems for nutrients and endogenous compounds (ie, hexose, amino acid, monocarboxylic acid, amine, nucleoside, and peptide transport systems) to transport agents across the blood-brain barrier.

• Conjugate a nontransportable drug to a blood-brain barrier transport vector, which is a modified protein- or receptor-specific antibody that undergoes receptor-mediated transcytosis, to penetrate the blood-brain barrier.

• Use nanoparticles that consist of colloidal polymer particles with a desired peptide absorbed on the surface and coated with polysorbate 80, and which can cross endothelial cells via endocytosis and enter the brain.

Immunotherapy

Immunotherapy utilizes a patient's immune system to achieve an antitumor effect. A variety of immunotherapeutic strategies have been investigated for their potential use in patients who have cancer with CNS involvement. These include therapeutic cancer vaccines, cellular immunotherapy with adoptive T-cell transfer (ACT) or chimeric antigen receptor (CAR) T-cell transfer, and blockade of immune checkpoint molecules using immune checkpoint antibodies (monoclonal antibodies).

The immune system and the blood-brain barrier

Immunotherapeutic agents were previously thought to be ineffective in patients with primary or metastatic CNS tumors, because of a purported inability to penetrate the blood-brain barrier.[39] In addition, the brain and the eye were considered "immunologically privileged," since these organs may be able to selectively block the entry of immune cells in order to limit immune-mediated damage from inflammation.[40] This concept was supported by studies in murine models, where tumors injected into the CNS grew preferentially compared with those injected intramuscularly or subcutaneously.[41] However, more recently, it has been demonstrated that inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activiation and infiltration of tumors.[5] Infiltrating immune cells may consist of professional antigen-presenting cells, including dendritic cells and cFlls of the innate immune system. However, the potential of these cells may be thwarted by the upregulation of various inhibitory immune checkpoint pathway-including indoleamine 2,3-dioxygenase 1, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1)-and by infiltration of other immunosuppressive cell populations, such as T regulatory cells.[41]

Cancer vaccines

Cancer vaccines are designed to activate and expand tumor-reactive T cells, by codelivering intrinsic tumor antigens or tumor neoantigens with an adjuvant formulation usually containing dendritic cells aimed at stimulating T-cell expansion. In a clinical trial of a dendritic cell–based vaccine loaded with glioblastoma-associated peptides, 60% of patients exhibited a vaccine-specific immune response; however, less than 10% demonstrated tumor regression and no overall survival benefit was seen.[42] This highlights a key challenge of vaccine therapies for cancer: the immunologic antitumor response is not of sufficient magnitude to generate clinically relevant outcomes. Another challenge is that tumor cells may share self-antigens with normal tissues, and this may precipitate on-target adverse events.[42] The next generation of cancer vaccines, however, will be developed from resected tumors, in the hope of facilitating a more personalized approach. In addition, whole-genome sequencing of tumor cells and peptide–major histocompatibility complex affinity algorithms may identify antigens able to elicit an anticancer immune response. This information can be used to create an effective individualized vaccine against tumor-rejection peptides.[41]

Cellular immunotherapy

Cellular immunotherapy aims to bypass the challenges of manipulating a patient’s existing antitumor immune response by reinfusing his or her own exogenously activated tumor-specific autologous T cells. The ACT method identifies and isolates tumor-specific T cells either from the peripheral blood or surgically resected tissue. In some cases, reinfused T cells may also be modified ex vivo before reinfusion, using vectors that encode a desired T-cell receptor or CAR.[43] ACT has demonstrated efficacy in patients with advanced melanoma, while CARs targeting CD19 have been efficacious in CD19-positive lymphoid malignancies.[44] ACT has been studied in 11 patients with recurrent glioblastoma who were treated with cytomegalovirus-specific T cells, since selected glioblastoma tumors may express cytomegalovirus antigens.[45] Early promising data from this select patient population have formed the basis for a larger study of this approach (ClinicalTrials.gov identifier: NCT00693095). Preclinical studies of CAR T cells against endothelial growth factor receptor variant III and human epidermal growth factor receptor 2 in primary brain tumors have supported the development of early clinical studies of these agents.[41]

Immune checkpoint blockade

During the past decade, the FDA has approved four immune checkpoint monoclonal antibodies as monotherapy, and combination therapy with two immune checkpoint monoclonal antibodies against PD-1 and cytotoxic T-lymphocyte–associated antigen 4, respectively, after clinical studies demonstrated significant efficacy with these agents in a variety of cancer types (Table 4).[46] Ongoing clinical trials of immune checkpoint monoclonal antibodies against a number of coinhibitory and costimulatory immune checkpoint molecules, both as monotherapy and in combination with both standard and investigational therapies, are being conducted in a number of different tumor types, including in patients with both newly diagnosed and recurrent primary CNS tumors. Currently, no efficacy data are available from these studies. Encouraging preliminary information has emerged from animal brain tumor models, suggesting that the combination of stereotactic radiation (to release neoantigens) and immune checkpoint monoclonal antibodies demonstrates significantly improved survival.[47] This has triggered a series of new clinical studies in patients with primary and metastatic brain tumors. Additional information about the potential benefits of immunotherapy in CNS cancers is available from studies in patients with brain metastases. Ipilimumab was investigated in 146 patients with asymptomatic brain metastases from melanoma. The median progression-free and overall survival times of these patients were 2.8 months and 4.3 months, respectively, and about 20% of patients were alive 1 year after beginning treatment.[48] Another study of ipilimumab in patients with asymptomatic brain metastases from melanoma reported a 27% CNS control rate, compared with a 10% control rate in patients with symptomatic brain metastases.[49] These studies suggest that ipilimumab could provide durable benefit in selected patients with brain metastases.

Anti_PD-1 therapy is also being investigated in patients with brain metastases. Pembrolizumab therapy in patients with PD-L1–positive melanoma and non–small-cell lung cancer with brain metastases resulted in 22% and 33% rates of response in the brain, respectively.[50] In a recent publication by Bouffet and colleagues, pediatric patients with recurrent glioblastoma from biallelic mismatch repair deficiency were found to demonstrate durable responses to anti–PD-1 therapy, which correlated with higher mutational and neoantigen load in these tumors.[51] These data and other encouraging early-phase studies in adult glioblastoma patients have laid the foundation for ongoing phase III trials comparing nivolumab and the combination of nivolumab and ipilimumab in recurrent glioblastoma, compared with bevacizumab (ClinicalTrials.gov identifier: NCT02017717) and nivolumab vs temozolomide plus brain radiation in patients with newly diagnosed glioblastoma (ClinicalTrials.gov identifier: NCT02617589).

Conclusions

Despite decades of effort, delivering effective doses of antineoplastic therapies to the CNS remains a major obstacle to improving outcomes in patients with primary and metastatic brain tumors. This is largely attributable to the efficiency of the blood-brain barrier in preventing the vast majority of chemotherapeutic agents from reaching therapeutic concentrations within the CNS. As a result, progress in the management of brain cancers has been substantially slower than that for patients with other systemic malignancies. Given the rapidly fatal nature of brain cancer and the paucity of effective therapies, many promising new agents have been rushed into clinical efficacy trials without documention of their ability to penetrate the CNS. The results of these studies are often uninformative, given that negative outcomes could be expected with either an inactive drug or an active drug that failed to achieve therapeutic concentrations at its target. A more rational approach would be to use one of the study designs described in this review, in order to efficiently determine intracranial drug concentrations before proceeding with early efficacy trials.

We have described approaches to purposefully designing drugs to be more likely to pass through the blood-brain barrier, as well as novel methods of delivering drugs to the CNS, bypassing the blood-brain barrier. One important and often overlooked observation is that the integrity of the blood-brain barrier appears to be modifiable, in that it can be made more permeable with radiation, focused ultrasound, and vasoactive peptides; and less permeable with glucocorticoids and vascular endothelial growth factor-targeted agents. A better understanding of the permeability of the blood-brain barrier-and novel techniques to adjust this permeability-would greatly improve therapeutic options for patients with established primary and metastatic brain tumors, and would provide a means of reducing the rapidly rising incidence of isolated CNS relapse in patients with systemic malignancies. A second potentially important observation is that lymphocytes readily cross the blood-brain barrier. As a result, immunotherapy represents a novel approach to cancer therapy that is of particular interest in neuro-oncology. Efforts are underway to study the efficacy of vaccines and immune checkpoint inhibitors in patients with primary or metastatic CNS tumors. The results of these ongoing studies will ultimately determine whether immunotherapy can substantially alter the outcome of patients with CNS malignancies.

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.

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