Cover Story

Breaching the blood–brain barrier: Researchers intensify quest for ‘holy grail of neuro-oncology’

The rapid development of gene sequencing and targeted cancer treatments has allowed oncologists to deliver highly effective personalized therapies with near-pinpoint accuracy, killing tumor cells and sparing healthy ones.

Despite these advances, the biological equivalent of a brick wall — the blood–brain barrier — has remained almost impenetrable.

Consequently, although patients with many types of cancer are living longer than ever, survival for those with primary brain tumors or brain metastases has not improved significantly since the 1980s.

Traditionally, the only way around the blood–brain barrier — a protective layer of interlocking cells that prevents toxins and other infectious agents from entering brain tissue or attacking the central nervous system — has been through intracerebroventricular administration, an excruciating process in which drugs are delivered through a hole drilled in the skull. However, therapies delivered in this manner only reach the brain’s surface, likely leaving deeper tumors untreated.

Hence the buzz when Todd Mainprize, MD, FRCPC, a neurosurgeon at Sunnybrook Health Science Centre in Toronto and assistant professor in the division of neurosurgery at University of Toronto, and colleagues announced in November that they noninvasively breached the blood–brain barrier in a human for the first time.

“This will help facilitate treatment of brain tumors in the future by allowing us to get the drugs to the right area in hopes of improving the outcomes of these patients,” Mainprize told HemOnc Today.

HemOnc Today spoke with oncologists and neurosurgeons about the effort to identify techniques capable of breaching the blood–brain barrier, the challenges encountered so far, and the possibility that the breakthrough by Mainprize and colleagues means researchers are on the brink of momentous therapeutic advances.

Incidence and survival

An estimated 23,770 people in the United States will be diagnosed with primary brain tumors or other CNS cancers in 2016, according to SEER data. If trends from the past decade persist, only one-third of them will survive 5 years.

An additional 170,000 to 200,000 Americans with other primary cancer types learn each year that they have developed brain metastases, according to the American Brain Tumor Association. Lung cancer, breast cancer, melanoma, colon cancer and kidney cancer are most likely to spread to the brain.

“Brain metastases will occur in 30% to 40% of all patients with cancer,” Mainprize said. “Over the last several years, there has been a significant improvement in the outcome of certain types of cancer because of improved systemic therapy, so patients are living longer. These patients are getting more tumors in their brains because they are living longer.”

Median survival of untreated patients with brain metastases is about 1 month, according to the International RadioSurgery Association. Whole-brain radiation therapy — the most common treatment for brain metastases — typically extends survival to about 4 months.

The addition of surgery to whole-brain radiation therapy can further prolong survival, but it carries risks for postoperative morbidity and other complications, such as infections or hemorrhages. It also is not curative.

The chemotherapy agent temozolomide, which can cross the blood–brain barrier, is a common treatment option. However, response rates are only about 7% in patients who have not received prior chemotherapy.

“Patients are doing better and living longer, and you are expanding the lifetime of a tumor once metastatic within a patient,” Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center and a professor of medicine at NYU Langone Medical Center, told HemOnc Today. “The end stage for patients who are treated with some of these novel agents, unfortunately, involves diffuse metastases to the central nervous system and leptomeninges, and they have been nearly impossible to treat.”

Jeffrey S. Weber, MD, PhD
Jeffrey S. Weber

Consequently, the ability to identify new techniques to treat primary brain tumors — as well as control or eradicate brain metastases — has become an area of intense research.

“Much of the chemotherapy that we use to treat these patients is not getting to the tumor cells themselves,” Mainprize said. “One of the ‘holy grails’ of neuro-oncology is not only to develop an effective treatment, but to make sure it gets delivered where it is effective, which is in the tumor cells of the brain.”

Some agents have demonstrated the potential to effectively treat primary or metastatic brain tumors. However, the blood–brain barrier has hindered delivery of these treatments.

The barrier is composed of tight junctions between microvascular endothelial cells. These junctions limit penetration: Essential nutrients are allowed in, but larger, nonlipid soluble particles require a protein for transport to get across.

A review by William M. Pardridge, MD, published in Neurotherapeutics, suggested nearly all large-molecule drugs and more than 98% of small-molecule drugs developed to treat brain disorders are unable to cross the blood–brain barrier.

Further, any substrate molecules that are able to pass the first layer are quickly removed by a drug-resistant, gene-encoded protein.

This creates what Pardridge called a “bottleneck in brain drug development.”

“There are two schools of thought,” Sadhana Jackson, MD, assistant clinical investigator in the neuro-oncology branch at the NCI’s Center for Cancer Research, told HemOnc Today.

Some researchers give up on agents that demonstrate efficacy but cannot breach the blood–brain barrier, according to Sadhana Jackson, MD.
Some researchers give up on agents that demonstrate efficacy but cannot breach the blood–brain barrier, according to Sadhana Jackson, MD. “Then there are people like me who say, ‘If it can’t get in but it still kills, we need to find a way to get it in there,’” she said.

Photo by Ernie Branson

“There are people who say, ‘If a drug can get through the barrier and kill [cancer cells], it is a good drug, but if a drug just kills but cannot get through, then let’s move on,’” Jackson said. “Then there are people like me who say, ‘If it can’t get in but it still kills, we need to find a way to get it in there.’”

Methods exist that allow clinicians to breach the barrier. However, these methods often are wrought with serious toxicities.

For example, although administering mannitol through the arteries has been shown to increase drug delivery to brain tumors two- to sixfold, its use can lead to convulsions and decreased cognitive function.

Another approach involves the surgical insertion of a catheter into the brain, which allows for a convection-enhanced drug delivery under a constant pressure gradient. However, randomized trials of this approach have yet to demonstrate a survival benefit.

Although some research focuses on developing effective drugs, the emphasis should also be on identifying better ways to safely deliver them, Jackson said.

“There are more scientists looking at other problems — like genetic problems and inherent differences in the tumor environment — but delivery is one area that certainly needs more research,” she said.

A complex approach

Breaching the blood–brain barrier is a formidable challenge in the treatment of any neurological disorder. However, it can be more complex when the goal is to treat a tumor.

“What’s also important is to evaluate the amount and distribution of drug entry when it’s given systemically. In different areas of the tumor, drug concentrations can vary based on tumor size, location and vascularity,” Jackson said.

As tumors evolve and grow, the structure of the blood–brain barrier becomes increasingly inconsistent.

Because malignant tumors have increased angiogenesis, they create a web of abnormal blood vessels that can weaken the blood–brain barrier.

Research from Watkins and colleagues — published in 2014 in Nature Communications — showed glioblastoma cells outside the tumor mass take over blood flow and nutrients that would be directed toward astrocytes, or brain cells, of the blood–brain barrier. This process appeared to weaken the tight junctions of the barrier, making it “leaky.”

Although researchers initially thought this process would make the barrier more vulnerable to drugs delivered to the brain in the blood, treating tumors actually is more difficult because the barrier becomes heterogeneous. The barrier can be easier to penetrate in some parts but not others, making drug delivery far more inconsistent and allowing a tumor to persist.

“If there is a tumor in the brain that is enhancing with some of the contrast images we have, that is already an indication that the blood–brain barrier has been compromised,” James R. Connor, PhD, distinguished professor of neurosurgery, neural and behavioral sciences, and pediatrics, as well as vice chair of neurosurgery research at Penn State Hershey, told HemOnc Today. “Some of the drugs we have may be able to access that tumor. But some of the other tumors that are not enhancing yet are the ones that are going to be problematic, whether it is a primary tumor or the first metastatic tumor.”

Phase 2 and phase 3 studies designed to evaluate targeted agents specific to aberrant signaling pathways in high-grade gliomas have been disappointing, according to Manmeet Ahluwalia, MD, FACP, director of the brain metastasis research program at Cleveland Clinic and a HemOnc Today Editorial Board member.

Manmeet Ahluwalia, MD, FACP
Manmeet Ahluwalia
Photo by Tom Merce ©Cleveland Clinic 2016.

“In addition to the difficulty of delivering agents across the blood–brain barrier, there are other challenges that limit the efficacy of these agents,” Ahluwalia told HemOnc Today. “These include accounting for the heterogeneity of tumors, redundancy of pathway interactions, a lack of accurate and reproducible biomarkers to select patients for specific therapies, and difficulty assessing target modulation.”

Ultrasound, laser technology

Mainprize and colleagues focused their research on the use of ultrasound to breach the blood–brain barrier for decades.

However, the biggest challenge with this approach was figuring out “how to get ultrasound waves through the thick skull without them being useless by the time they got across the skull,” he said.

Kullervo Hynynen, PhD, director of physical sciences at Sunnybrook Research Institute, provided tremendous insights to overcome that challenge.

Hynynen worked with InSightec for nearly 2 decades to develop focused ultrasound technology and bring it to the clinic. He was the first to pair MRI with focused ultrasound, and then to show that focused ultrasound coupled with microbubbles could locally and reversibly disrupt the blood–brain barrier.

“He has made significant calculations based on the curvature of the skull in each individual,” Mainprize said. “Every patient gets a CT scan of the skull, and we look at the skull thickness, curvature [and other factors]. He used the skull as a landing to help focus the ultrasound waves. It’s tailored to each patient.”

Last fall, Mainprize and colleagues used this technology to noninvasively breach the blood–brain barrier of 56-year-old Bonny Hall.

Hall — who has glioblastoma — wore a special helmet with approximately 1,000 ultrasound transducers aimed to various areas of the brain to focus the ultrasound waves.

Investigators then injected the chemotherapy agent doxorubicin along with gas-filled microbubbles into her bloodstream. When a beam of focused ultrasound waves was applied to her skull, the bubbles vibrated, allowing them and the doxorubicin to force their way through the blood–brain barrier.

“Those bubbles will oscillate in size from small to big, and when they get big, they pop open the connections between the endothelial cells and breach the blood–brain barrier,” Mainprize said. “These air bubbles that oscillate in size tear those connections open so there is space between these cells, just like there is everywhere else in the body.”

The tight junctions in the blood–brain barrier loosened after the ultrasound delivery, began reforming within 6 hours and returned to their normal state within 24 hours.

“We can reach the blood–brain barrier selectively — meaning anywhere in the brain — and noninvasively, meaning we do not have to stick a catheter in the brain or put a wire in to the arteries of the brain,” Mainprize said. “We can do it in real time, meaning we can watch what we’re doing on the MRI scanner, and it is reversible. In about 6 to 8 hours, the breaching of the blood–brain barrier reseals.”

Researchers treated Hall as part of a phase 1 safety trial that will include up to 10 more patients with brain cancer. Mainprize and colleagues also intend to conduct a trial in brain metastases of patients with certain types of breast cancer.

“There are some very good drugs available, but those drugs don’t get into the brain,” Mainprize said. “If we open up the blood–brain barrier in some of these patients, they may not require radiation or surgery.”

A phase 1 study by Carpentier and colleagues — published in June in Science Translational Medicine — used a similar technique to breach the blood–brain barrier in 15 patients with recurrent glioblastoma. The researchers used an implantable ultrasound device (SonoCloud, CarThera) to deliver sound waves that cause inserted microbubbles to vibrate and temporarily open the blood–brain barrier.

Patients in this trial received carboplatin, and although the study was not designed to evaluate treatment efficacy, nine patients demonstrated stalled tumor growth. The device only takes 2 minutes to open the blood–brain barrier for 6 hours, and it can increase the concentration of medicine five- to sixfold.

“The walls of the blood vessels in the brain are very difficult to cross for certain molecules,” Frederic Sottilini, CEO of CarThera, said in a press release. “Scientists have been researching ways to bypass this barrier for over 50 years. This could mean major therapeutic advances, not only for brain cancers, but also for neurodegenerative disease such as Alzheimer’s.”

In another trial, Eric C. Leuthardt, MD, professor of neurosurgery at Washington University in St. Louis, and colleagues used hyperthermic laser ablation to break down the blood–brain barrier in 14 patients with recurrent glioblastoma. The device — approved for use as a surgical tool to treat brain tumors — involves a laser-tipped probe that heats and kills tumor cells.

Data from their pilot study — published in February in PLoS ONE — showed a peak of high permeability within 1 to 2 weeks after laser ablation and closing by 4 to 6 weeks, thus creating a “therapeutic window.” Patients received doxorubicin during this time.

“Not only are you killing the tumor, you are actually opening up a window of opportunity to deliver various drugs and chemicals and therapies that could otherwise not get there,” Leuthardt said in a press release. “The blood–brain barrier is a two-way street. By breaking it down, you can get things into the brain, but ... now things can go from your brain into your circulation to your peripheral system, which includes your immune system.”

Consequently, although this technique is more invasive than ultrasound, laser therapy can enhance immunotherapy to treat brain tumors, Leuthardt said.

Potential implications

Despite these advances, other experts have cautioned against claiming victory.

Because the blood–brain barrier may be weakened simply by the presence of a tumor, statements that the barrier truly can be “breached” should be viewed carefully, Connor said.

“When people report that their drug or their compound is getting across the blood–brain barrier and that it is in the tumor, it’s misleading,” Connor said. “They are saying, ‘We can get the drug into the tumor,’ but it is not crossing the blood–brain barrier. Rather, it is crossing a compromised blood–brain barrier.”

The ultrasound method, like traditional administration of mannitol, still can be dangerous, Connor emphasized.

Although they may help open the blood–brain barrier to therapeutic agents, they also open it — albeit temporarily — to viruses, bacteria and other foreign substances that typically are blocked. Bacteria in the brain can lead to meningitis, which often is fatal.

“I’m always sensitive to put it this way, but [these methods] induce a microbleed,” Connor said. “If you weren’t doing it in the context of trying to get a drug into the brain, it would be considered a bad thing. ... Although temporarily effective, these are still not the optimal answers.”

Control is the critical factor, Hynynen said.

“We and others have shown many times that by properly controlling the exposure, there are no bleeds or extravasations of erythrocytes,” he said. “There are now many papers that have shown repeated opening of the blood-brain barrier without any short- or long-term effects on the brain.”

Researchers still need to investigate the potential risks of opening the blood-brain barrier, Mainprize said.

“The possibility of it causing a long-term problem, in terms of a virus getting in and somebody having some memory problems, is probably less of a concern than the immediate threat to the patient with the malignant brain cancer,” he said. “We are concerned about all of the potentials, but just like anything in medicine, you have to start somewhere. We are doing everything we can to ensure that we’re following the patient to make sure there are no adverse events.”

Moreover, focused ultrasound has a crucial advantage over other methods.

“The main benefit of the focused ultrasound method is that the drugs can be delivered into an MRI–targeted location in the brain while the rest of the brain is not exposed to the drug,” Mainprize said. “It cannot be overstated that the ability to open small or larger areas anywhere in the brain selectively is an important feature. Most other methods are semi-selective at best.”

Although these methods are still under investigation as options to treat primary and metastatic brain tumors, the pursuit of techniques to cross the blood–brain barrier noninvasively — without compromising its function — continues.

Connor is involved with a study in which researchers are evaluating use of engineered liposomes for transcytosis, a form of transcellular transport that is being evaluated as a method to improve drug delivery without having to breach the blood–brain barrier.

“The most significant advantage with this approach is the liposomes cross the blood–brain barrier while it is intact and can be a surveilling approach, where we can possibly identify these cancer cells before they become a tumor and compromise the barrier,” Connor said. “That is obviously a goal. We’re not there yet, but ideally we can detect cancer cells or smaller tumors where we can develop an intervention — something we can offer the patient as a mechanism other than ‘wait and see’ when you have a potentially fatal disease.”

Other therapeutic advances

Other therapeutic agents have demonstrated potential, albeit in small studies.

Aldoxorubicin (CytRx), an albumin–drug conjugate, is under investigation in a phase 2, open-label, multisite trial of 28 patients with unresectable glioblastoma multiforme. All patients experienced disease progression after prior treatment with surgery, radiation and temozolomide.

Patients received IV doses of 350 mg/m2 (n = 6) or 250 mg/m2 (n = 22) on day 1, followed by every 21 days thereafter until discontinuation (range of doses, 1-20).

Morris D. Groves, MD, neuro-oncologist at Texas Oncology–Austin Brain Tumor Center, and colleagues presented data at the ASCO Annual Meeting that showed three patients achieved partial responses and seven patients achieved stable disease. Median OS was 8.6 months (95% CI, 7.8-10.1), and seven patients remained on follow-up.

The treatment appeared to be well tolerated without evidence of CNS toxicity or clinically significantly cardiac toxicity.

Researchers observed no viable tumor tissue in a pathology analysis of two patients who underwent surgery following aldoxorubicin treatment.

“The findings from this trial are early but exciting,” Groves said in a press release. “The finding of no tumor cells in the resected glioblastoma multiforme tumor samples after treatment with aldoxorubicin is worth further investigation. This suggests — somewhat paradoxically — that by binding to albumin, aldoxorubicin may allow doxorubicin to cross the blood–brain barrier and into the malignancy.”

Jackson and colleagues also are evaluating drugs that can be used in combination with chemotherapy to ensure better passage across the blood–brain barrier.

“If there is an impermeable drug that does a great job of killing these cells, then maybe we can give an additional drug that can open the blood–brain barrier and allow the chemotherapy easy passage to the tumor,” Jackson said.

Her team at the NCI is conducting a small pilot study looking at the drug regadenoson, an adenosine receptor agonist. This work builds on a study of a bradykinin analog, Cereport, conducted in the late 1990s at the NIH and Children’s National Medical Center.

“Cereport given to rodents could open the blood–brain barrier to increase carboplatin delivery but, when the combination was given to humans, they saw no increase in OS or PFS,” Jackson said. “They thought the study failed but what they didn’t look for was how much more drug got into the brain. They just wanted to measure survival. As a result, the drug was thrown by the wayside.”

More research should focus on how much of a drug gets into the brain rather than simply assessing survival, she added.

“It may be that more of a drug gets into the brain but also comes back out because, once you open the blood–brain barrier, it may not be a one-way street,” Jackson said. “If we can monitor how much gets in and how much gets out, we might be able to gain perspective on the permeability coefficient — a box we really need to check off.”

Immunotherapies also are being evaluated for their potential to cross the blood–brain barrier in patients with melanoma, a disease in which incidence of brain metastases is “astronomical,” according to Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of hematology and oncology at St. Luke’s Cancer Center and a HemOnc Today Editorial Board member.

Sanjiv S. Agarwala, MD
Sanjiv S. Agarwala

Research by Margolin and colleagues showed ipilimumab (Yervoy, Bristol-Myers Squibb) induced similar response rates in the brain and outside the brain.

“We always thought that the brain was an immunologically privileged organ, meaning that immunotherapy would not work there,” Agarwala said during a presentation at the HemOnc Today Melanoma and Cutaneous Malignancies meeting in New York. “This is the first example of an immunotherapy working in the brain, which was a major breakthrough.”

The ongoing ABC trial is evaluating nivolumab (Opdivo, Bristol-Myers Squibb) with or without ipilimumab in patients with brain metastases. The trial includes patients who were previously untreated and asymptomatic, as well as those who were previously treated and symptomatic.

Another study has been designed to assess the anti–PD-1 therapy pembrolizumab (Keytruda, Merck) in patients with brain metastases. The preliminary results of this study have shown promising results in non–small cell lung cancer and melanoma brain metastases.

The efficacy of immunotherapy in the brain may call into question the existence of the blood–brain barrier once a cancer has metastasized.

“Breaching the blood–brain barrier is an interesting idea, but does the barrier actually exist once you have an invasive tumor?” Weber said. “Does it play an important role in excluding cells for adoptive cell therapy, for drugs, for antibodies, etc, that’s not breached by the presence of a tumor? It’s not 100% obvious that there is an intact barrier in someone with metastatic cancer.”

Still, these data suggest that there is a new paradigm evolving for brain metastases, an area for which researchers had always tended to give up hope, Agarwala said.

“Responses you are getting outside of the brain, you may be able to reproduce inside the brain,” Agarwala said. “What this is telling us, overall, is that maybe the brain is becoming just another organ.” – by Kristie L. Kahl and Anthony SanFilippo

References:

ABTA document (stats). Available at: www.abta.org/secure/metastatic-brain-tumor.pdf. Accessed July 5, 2016.

Bellavance M-A, et al. APPS J. 2008;doi:10.1208/s12248-008-9018-7.

Carpentier A, et al. Sci Transl Med. 2016;doi:10.1126/scitransmed.aaf6086.

Grabrucker AM, et al. Curr Top Med Chem. 2013;doi:10.1007/7355_2013_22.

Groves MD, et al. Abstract 2027. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Healy AT and Vogelbaum MA. Surg Neurol Int. 2015;doi:10.4103/2152-7806.151337.

Jain KK. Nanomedicine. 2012;7:1225-1233.

Leuthardt EC, et al. PLoS ONE. 2016;doi:10.1371/journal.pone.0148613.

Long GV, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70431-X.

Margolin K, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70090-6.

Nussbaum ES, et al. Cancer. 1996;78:1781-1788.

Pardridge W. NeuroRx. 2005;doi:10.1602/neurorx.2.1.3.

Reardon DA, et al. Abstract 2009. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Watkins S, et al. Nat Commun. 2014;doi:10.1038/ncomms5196.

For more information:

Sanjiv S. Agarwala, MD, can be reached at ssagarwala0501@gmail.com.

Manmeet Ahluwalia, MD, FACP, can be reached at ahluwam@ccf.org.

James R. Connor, PhD, can be reached at jconnor@hmc.psu.edu.

Kullervo Hynynen, PhD, can be reached at khynynen@sri.utoronto.ca.

Sadhana Jackson, MD, can be reached at sadhana.jackson@nih.gov.

Todd Mainprize, MD, FRCPC, can be reached at todd.mainprize@sunnybrook.ca.

Jeffrey S. Weber, MD, PhD, can be reached at jeffrey.weber2@nyumc.org.

Disclosure: Agarwala, Ahluwalia, Connor, Hynynen, Jackson, Mainprize and Weber report no relevant financial disclosures.

 

POINTCOUNTER

Should breaching the blood–brain barrier remain a research priority in light of advances in immunotherapy?

POINT

Breaching the blood–brain barrier may not be as important for cellular immunotherapy, but it is for drugs. Consequently, it needs to remain a research priority.

Immune cells can get into the brain, but if you are giving drugs that have antibodies like the checkpoint blockers, then the blood–brain barrier can be a problem.

Rakesh K. Jain, PhD
Rakesh K. Jain

In glioblastoma, for decades, very little has happened in terms of improving OS. The only recent development is the tumor treating fields device (Optune, Novocure), a device that people have to wear on their heads every day that improves survival. Further, bevacizumab (Avastin, Genentech) — which a lot of people were putting their hopes on — did not improve OS in randomized phase 3 trials.

A hallmark of glioblastoma is leaky blood vessels. If you have leaky vessels, then drug delivery should not be a problem. But when a number of these cancer cells take over the normal blood vessels, and if these vessels still have an intact blood–brain barrier, unfortunately recurrent growth occurs around these co-opted vessels.

This is where finding a way to break down the blood–brain barrier would help — not in the primary tumor, but in these lesions that are around the normal vessels. Those are the areas where vessels do not leak, and yet those are the regions where cancer cells can grow and ultimately lead to death.

In those areas, it would be good to know how to get past the blood–brain barrier, especially with the checkpoint blockers. However, for therapies such as vaccines — which are injected directly into the brain, where you are relying on immune cells — it is a different process.

There are two kinds of immunotherapies. The one that is cell based is fine. With the other, you need a drug or an antibody to penetrate the brain. The latter is where you need to worry about the blood–brain barrier, and that is the area where research needs to remain an important priority.

Rakesh K. Jain, PhD, is Andrew Werk Cook professor of tumor biology at Harvard Medical School and director of E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital. He can be reached at rjain@mgh.harvard.edu. Disclosure: Jain reports no relevant financial disclosures.

COUNTER

The landscape for research must change, and immunotherapy must be on the forefront.

A major therapeutic hurdle for glioblastoma has been the remarkable molecular heterogeneity within tumors. It is not surprising that cytotoxic chemotherapy has achieved only limited benefit, and targeted agents — even in combination — have failed to dramatically impact tumor control.

Douglas E. Ney, MD
Douglas E. Ney

It has long been felt that harnessing a person’s own immune system may be key to fighting cancer. Indeed, this is proving to be true. Over the past several years, advances in the understanding and development of immunological therapies have resulted in remarkable outcomes and have become the most exciting area in oncology today.

Drugs targeting the cytotoxic T-lymphocyte–associated protein 4 (CTLA4) and the programmed cell death protein 1/programmed death-ligand protein (PD-1/PD-L1) have resulted in unprecedented survival benefits and dramatic clinical responses against a range of cancer types.

These checkpoint inhibitors have resulted in long-term survival for patients with metastatic melanoma, a deadly and typically treatment refractory disease, not unlike glioblastoma. Similar immunotherapies may benefit patients with brain tumors, as tumors like glioblastoma are highly immuno-active and frequently have high PD-1 expression. Trials involving checkpoint inhibitors in patients with glioblastoma are ongoing and the results are eagerly awaited.

Recent results of the ReACT study confirm enthusiasm for immunotherapeutic therapies. In this study, 70 patients with glioblastoma at first or second recurrence received either bevacizumab plus placebo, or bevacizumab plus the EGFRvIII vaccine rindopepimut (Celldex Therapeutics). In this double blind, randomized, placebo-controlled study, patients who received rindopepimut achieved a significantly longer OS (11.3 months vs. 9.3 months; HR = 0.53, P = .0137). Further, prolonged and durable responses were seen in the rindopepimut-treated group, with 24-month OS rates of 25% in that group vs. 0% in patients who received bevacizumab plus placebo. Notably, this is the first randomized clinical trial to demonstrate a survival benefit in patients with glioblastoma using immunotherapy.

ICT-107 (ImmunoCellular Therapeutics) is an autologous dendritic cell vaccine that targets six different glioblastoma-associated antigens. Results of a phase 2 trial showed that PFS was improved by 2 months in patients who received ICT-107 (P = 0.006) compared with patients who received a matched control vaccine. Perhaps more intriguingly, in a subset of patients who were HLA-A2 positive and MGMT methylated, PFS was significantly improved (24.1 vs. 8.5 months; HR = 0.26; P = .005). Data were too immature (with median follow-up of approximately 16 months) at the time of reporting to determine if a survival benefit was achieved. These results have led to a new and ongoing randomized phase 3 trial that should shed light on the benefit of this therapy.

Numerous other immunologic trials are ongoing, and they represent the future of the field of neuro-oncology. Glioblastoma is an incredibly complex and difficult disease, and it will require a multidisciplinary effort to achieve tangible success, but we are ever closer. Immunological therapies need to remain at the forefront of neuro-oncology research. We have made tremendous gains, with even further strides to go, and it is clear that our efforts need to concentrate on this new area where we are just starting to see success.

References:

Reardon DA, et al. Neuro Oncol. 2015;doi:10.1093/neuonc/nov178.

Reardon DA, et al. Abstract IMCT-08. Presented at: Society for Neuro-Oncology Annual Meeting; Nov. 19-22, 2015; San Antonio, Texas.

Wen P, et al. Abstract 2005. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Douglas E. Ney, MD, is associate professor in the department of neurology at University of Colorado School of Medicine. He can be reached at douglas.ney@ucdenver.edu. Disclosure: Ney reports no relevant financial disclosures.

The rapid development of gene sequencing and targeted cancer treatments has allowed oncologists to deliver highly effective personalized therapies with near-pinpoint accuracy, killing tumor cells and sparing healthy ones.

Despite these advances, the biological equivalent of a brick wall — the blood–brain barrier — has remained almost impenetrable.

Consequently, although patients with many types of cancer are living longer than ever, survival for those with primary brain tumors or brain metastases has not improved significantly since the 1980s.

Traditionally, the only way around the blood–brain barrier — a protective layer of interlocking cells that prevents toxins and other infectious agents from entering brain tissue or attacking the central nervous system — has been through intracerebroventricular administration, an excruciating process in which drugs are delivered through a hole drilled in the skull. However, therapies delivered in this manner only reach the brain’s surface, likely leaving deeper tumors untreated.

Hence the buzz when Todd Mainprize, MD, FRCPC, a neurosurgeon at Sunnybrook Health Science Centre in Toronto and assistant professor in the division of neurosurgery at University of Toronto, and colleagues announced in November that they noninvasively breached the blood–brain barrier in a human for the first time.

“This will help facilitate treatment of brain tumors in the future by allowing us to get the drugs to the right area in hopes of improving the outcomes of these patients,” Mainprize told HemOnc Today.

HemOnc Today spoke with oncologists and neurosurgeons about the effort to identify techniques capable of breaching the blood–brain barrier, the challenges encountered so far, and the possibility that the breakthrough by Mainprize and colleagues means researchers are on the brink of momentous therapeutic advances.

Incidence and survival

An estimated 23,770 people in the United States will be diagnosed with primary brain tumors or other CNS cancers in 2016, according to SEER data. If trends from the past decade persist, only one-third of them will survive 5 years.

An additional 170,000 to 200,000 Americans with other primary cancer types learn each year that they have developed brain metastases, according to the American Brain Tumor Association. Lung cancer, breast cancer, melanoma, colon cancer and kidney cancer are most likely to spread to the brain.

“Brain metastases will occur in 30% to 40% of all patients with cancer,” Mainprize said. “Over the last several years, there has been a significant improvement in the outcome of certain types of cancer because of improved systemic therapy, so patients are living longer. These patients are getting more tumors in their brains because they are living longer.”

Median survival of untreated patients with brain metastases is about 1 month, according to the International RadioSurgery Association. Whole-brain radiation therapy — the most common treatment for brain metastases — typically extends survival to about 4 months.

The addition of surgery to whole-brain radiation therapy can further prolong survival, but it carries risks for postoperative morbidity and other complications, such as infections or hemorrhages. It also is not curative.

The chemotherapy agent temozolomide, which can cross the blood–brain barrier, is a common treatment option. However, response rates are only about 7% in patients who have not received prior chemotherapy.

“Patients are doing better and living longer, and you are expanding the lifetime of a tumor once metastatic within a patient,” Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center and a professor of medicine at NYU Langone Medical Center, told HemOnc Today. “The end stage for patients who are treated with some of these novel agents, unfortunately, involves diffuse metastases to the central nervous system and leptomeninges, and they have been nearly impossible to treat.”

Jeffrey S. Weber, MD, PhD
Jeffrey S. Weber

Consequently, the ability to identify new techniques to treat primary brain tumors — as well as control or eradicate brain metastases — has become an area of intense research.

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“Much of the chemotherapy that we use to treat these patients is not getting to the tumor cells themselves,” Mainprize said. “One of the ‘holy grails’ of neuro-oncology is not only to develop an effective treatment, but to make sure it gets delivered where it is effective, which is in the tumor cells of the brain.”

Some agents have demonstrated the potential to effectively treat primary or metastatic brain tumors. However, the blood–brain barrier has hindered delivery of these treatments.

The barrier is composed of tight junctions between microvascular endothelial cells. These junctions limit penetration: Essential nutrients are allowed in, but larger, nonlipid soluble particles require a protein for transport to get across.

A review by William M. Pardridge, MD, published in Neurotherapeutics, suggested nearly all large-molecule drugs and more than 98% of small-molecule drugs developed to treat brain disorders are unable to cross the blood–brain barrier.

Further, any substrate molecules that are able to pass the first layer are quickly removed by a drug-resistant, gene-encoded protein.

This creates what Pardridge called a “bottleneck in brain drug development.”

“There are two schools of thought,” Sadhana Jackson, MD, assistant clinical investigator in the neuro-oncology branch at the NCI’s Center for Cancer Research, told HemOnc Today.

Some researchers give up on agents that demonstrate efficacy but cannot breach the blood–brain barrier, according to Sadhana Jackson, MD.
Some researchers give up on agents that demonstrate efficacy but cannot breach the blood–brain barrier, according to Sadhana Jackson, MD. “Then there are people like me who say, ‘If it can’t get in but it still kills, we need to find a way to get it in there,’” she said.

Photo by Ernie Branson

“There are people who say, ‘If a drug can get through the barrier and kill [cancer cells], it is a good drug, but if a drug just kills but cannot get through, then let’s move on,’” Jackson said. “Then there are people like me who say, ‘If it can’t get in but it still kills, we need to find a way to get it in there.’”

Methods exist that allow clinicians to breach the barrier. However, these methods often are wrought with serious toxicities.

For example, although administering mannitol through the arteries has been shown to increase drug delivery to brain tumors two- to sixfold, its use can lead to convulsions and decreased cognitive function.

Another approach involves the surgical insertion of a catheter into the brain, which allows for a convection-enhanced drug delivery under a constant pressure gradient. However, randomized trials of this approach have yet to demonstrate a survival benefit.

Although some research focuses on developing effective drugs, the emphasis should also be on identifying better ways to safely deliver them, Jackson said.

“There are more scientists looking at other problems — like genetic problems and inherent differences in the tumor environment — but delivery is one area that certainly needs more research,” she said.

A complex approach

Breaching the blood–brain barrier is a formidable challenge in the treatment of any neurological disorder. However, it can be more complex when the goal is to treat a tumor.

“What’s also important is to evaluate the amount and distribution of drug entry when it’s given systemically. In different areas of the tumor, drug concentrations can vary based on tumor size, location and vascularity,” Jackson said.

As tumors evolve and grow, the structure of the blood–brain barrier becomes increasingly inconsistent.

Because malignant tumors have increased angiogenesis, they create a web of abnormal blood vessels that can weaken the blood–brain barrier.

Research from Watkins and colleagues — published in 2014 in Nature Communications — showed glioblastoma cells outside the tumor mass take over blood flow and nutrients that would be directed toward astrocytes, or brain cells, of the blood–brain barrier. This process appeared to weaken the tight junctions of the barrier, making it “leaky.”

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Although researchers initially thought this process would make the barrier more vulnerable to drugs delivered to the brain in the blood, treating tumors actually is more difficult because the barrier becomes heterogeneous. The barrier can be easier to penetrate in some parts but not others, making drug delivery far more inconsistent and allowing a tumor to persist.

“If there is a tumor in the brain that is enhancing with some of the contrast images we have, that is already an indication that the blood–brain barrier has been compromised,” James R. Connor, PhD, distinguished professor of neurosurgery, neural and behavioral sciences, and pediatrics, as well as vice chair of neurosurgery research at Penn State Hershey, told HemOnc Today. “Some of the drugs we have may be able to access that tumor. But some of the other tumors that are not enhancing yet are the ones that are going to be problematic, whether it is a primary tumor or the first metastatic tumor.”

Phase 2 and phase 3 studies designed to evaluate targeted agents specific to aberrant signaling pathways in high-grade gliomas have been disappointing, according to Manmeet Ahluwalia, MD, FACP, director of the brain metastasis research program at Cleveland Clinic and a HemOnc Today Editorial Board member.

Manmeet Ahluwalia, MD, FACP
Manmeet Ahluwalia
Photo by Tom Merce ©Cleveland Clinic 2016.

“In addition to the difficulty of delivering agents across the blood–brain barrier, there are other challenges that limit the efficacy of these agents,” Ahluwalia told HemOnc Today. “These include accounting for the heterogeneity of tumors, redundancy of pathway interactions, a lack of accurate and reproducible biomarkers to select patients for specific therapies, and difficulty assessing target modulation.”

Ultrasound, laser technology

Mainprize and colleagues focused their research on the use of ultrasound to breach the blood–brain barrier for decades.

However, the biggest challenge with this approach was figuring out “how to get ultrasound waves through the thick skull without them being useless by the time they got across the skull,” he said.

Kullervo Hynynen, PhD, director of physical sciences at Sunnybrook Research Institute, provided tremendous insights to overcome that challenge.

Hynynen worked with InSightec for nearly 2 decades to develop focused ultrasound technology and bring it to the clinic. He was the first to pair MRI with focused ultrasound, and then to show that focused ultrasound coupled with microbubbles could locally and reversibly disrupt the blood–brain barrier.

“He has made significant calculations based on the curvature of the skull in each individual,” Mainprize said. “Every patient gets a CT scan of the skull, and we look at the skull thickness, curvature [and other factors]. He used the skull as a landing to help focus the ultrasound waves. It’s tailored to each patient.”

Last fall, Mainprize and colleagues used this technology to noninvasively breach the blood–brain barrier of 56-year-old Bonny Hall.

Hall — who has glioblastoma — wore a special helmet with approximately 1,000 ultrasound transducers aimed to various areas of the brain to focus the ultrasound waves.

Investigators then injected the chemotherapy agent doxorubicin along with gas-filled microbubbles into her bloodstream. When a beam of focused ultrasound waves was applied to her skull, the bubbles vibrated, allowing them and the doxorubicin to force their way through the blood–brain barrier.

“Those bubbles will oscillate in size from small to big, and when they get big, they pop open the connections between the endothelial cells and breach the blood–brain barrier,” Mainprize said. “These air bubbles that oscillate in size tear those connections open so there is space between these cells, just like there is everywhere else in the body.”

The tight junctions in the blood–brain barrier loosened after the ultrasound delivery, began reforming within 6 hours and returned to their normal state within 24 hours.

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“We can reach the blood–brain barrier selectively — meaning anywhere in the brain — and noninvasively, meaning we do not have to stick a catheter in the brain or put a wire in to the arteries of the brain,” Mainprize said. “We can do it in real time, meaning we can watch what we’re doing on the MRI scanner, and it is reversible. In about 6 to 8 hours, the breaching of the blood–brain barrier reseals.”

Researchers treated Hall as part of a phase 1 safety trial that will include up to 10 more patients with brain cancer. Mainprize and colleagues also intend to conduct a trial in brain metastases of patients with certain types of breast cancer.

“There are some very good drugs available, but those drugs don’t get into the brain,” Mainprize said. “If we open up the blood–brain barrier in some of these patients, they may not require radiation or surgery.”

A phase 1 study by Carpentier and colleagues — published in June in Science Translational Medicine — used a similar technique to breach the blood–brain barrier in 15 patients with recurrent glioblastoma. The researchers used an implantable ultrasound device (SonoCloud, CarThera) to deliver sound waves that cause inserted microbubbles to vibrate and temporarily open the blood–brain barrier.

Patients in this trial received carboplatin, and although the study was not designed to evaluate treatment efficacy, nine patients demonstrated stalled tumor growth. The device only takes 2 minutes to open the blood–brain barrier for 6 hours, and it can increase the concentration of medicine five- to sixfold.

“The walls of the blood vessels in the brain are very difficult to cross for certain molecules,” Frederic Sottilini, CEO of CarThera, said in a press release. “Scientists have been researching ways to bypass this barrier for over 50 years. This could mean major therapeutic advances, not only for brain cancers, but also for neurodegenerative disease such as Alzheimer’s.”

In another trial, Eric C. Leuthardt, MD, professor of neurosurgery at Washington University in St. Louis, and colleagues used hyperthermic laser ablation to break down the blood–brain barrier in 14 patients with recurrent glioblastoma. The device — approved for use as a surgical tool to treat brain tumors — involves a laser-tipped probe that heats and kills tumor cells.

Data from their pilot study — published in February in PLoS ONE — showed a peak of high permeability within 1 to 2 weeks after laser ablation and closing by 4 to 6 weeks, thus creating a “therapeutic window.” Patients received doxorubicin during this time.

“Not only are you killing the tumor, you are actually opening up a window of opportunity to deliver various drugs and chemicals and therapies that could otherwise not get there,” Leuthardt said in a press release. “The blood–brain barrier is a two-way street. By breaking it down, you can get things into the brain, but ... now things can go from your brain into your circulation to your peripheral system, which includes your immune system.”

Consequently, although this technique is more invasive than ultrasound, laser therapy can enhance immunotherapy to treat brain tumors, Leuthardt said.

Potential implications

Despite these advances, other experts have cautioned against claiming victory.

Because the blood–brain barrier may be weakened simply by the presence of a tumor, statements that the barrier truly can be “breached” should be viewed carefully, Connor said.

“When people report that their drug or their compound is getting across the blood–brain barrier and that it is in the tumor, it’s misleading,” Connor said. “They are saying, ‘We can get the drug into the tumor,’ but it is not crossing the blood–brain barrier. Rather, it is crossing a compromised blood–brain barrier.”

The ultrasound method, like traditional administration of mannitol, still can be dangerous, Connor emphasized.

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Although they may help open the blood–brain barrier to therapeutic agents, they also open it — albeit temporarily — to viruses, bacteria and other foreign substances that typically are blocked. Bacteria in the brain can lead to meningitis, which often is fatal.

“I’m always sensitive to put it this way, but [these methods] induce a microbleed,” Connor said. “If you weren’t doing it in the context of trying to get a drug into the brain, it would be considered a bad thing. ... Although temporarily effective, these are still not the optimal answers.”

Control is the critical factor, Hynynen said.

“We and others have shown many times that by properly controlling the exposure, there are no bleeds or extravasations of erythrocytes,” he said. “There are now many papers that have shown repeated opening of the blood-brain barrier without any short- or long-term effects on the brain.”

Researchers still need to investigate the potential risks of opening the blood-brain barrier, Mainprize said.

“The possibility of it causing a long-term problem, in terms of a virus getting in and somebody having some memory problems, is probably less of a concern than the immediate threat to the patient with the malignant brain cancer,” he said. “We are concerned about all of the potentials, but just like anything in medicine, you have to start somewhere. We are doing everything we can to ensure that we’re following the patient to make sure there are no adverse events.”

Moreover, focused ultrasound has a crucial advantage over other methods.

“The main benefit of the focused ultrasound method is that the drugs can be delivered into an MRI–targeted location in the brain while the rest of the brain is not exposed to the drug,” Mainprize said. “It cannot be overstated that the ability to open small or larger areas anywhere in the brain selectively is an important feature. Most other methods are semi-selective at best.”

Although these methods are still under investigation as options to treat primary and metastatic brain tumors, the pursuit of techniques to cross the blood–brain barrier noninvasively — without compromising its function — continues.

Connor is involved with a study in which researchers are evaluating use of engineered liposomes for transcytosis, a form of transcellular transport that is being evaluated as a method to improve drug delivery without having to breach the blood–brain barrier.

“The most significant advantage with this approach is the liposomes cross the blood–brain barrier while it is intact and can be a surveilling approach, where we can possibly identify these cancer cells before they become a tumor and compromise the barrier,” Connor said. “That is obviously a goal. We’re not there yet, but ideally we can detect cancer cells or smaller tumors where we can develop an intervention — something we can offer the patient as a mechanism other than ‘wait and see’ when you have a potentially fatal disease.”

Other therapeutic advances

Other therapeutic agents have demonstrated potential, albeit in small studies.

Aldoxorubicin (CytRx), an albumin–drug conjugate, is under investigation in a phase 2, open-label, multisite trial of 28 patients with unresectable glioblastoma multiforme. All patients experienced disease progression after prior treatment with surgery, radiation and temozolomide.

Patients received IV doses of 350 mg/m2 (n = 6) or 250 mg/m2 (n = 22) on day 1, followed by every 21 days thereafter until discontinuation (range of doses, 1-20).

Morris D. Groves, MD, neuro-oncologist at Texas Oncology–Austin Brain Tumor Center, and colleagues presented data at the ASCO Annual Meeting that showed three patients achieved partial responses and seven patients achieved stable disease. Median OS was 8.6 months (95% CI, 7.8-10.1), and seven patients remained on follow-up.

The treatment appeared to be well tolerated without evidence of CNS toxicity or clinically significantly cardiac toxicity.

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Researchers observed no viable tumor tissue in a pathology analysis of two patients who underwent surgery following aldoxorubicin treatment.

“The findings from this trial are early but exciting,” Groves said in a press release. “The finding of no tumor cells in the resected glioblastoma multiforme tumor samples after treatment with aldoxorubicin is worth further investigation. This suggests — somewhat paradoxically — that by binding to albumin, aldoxorubicin may allow doxorubicin to cross the blood–brain barrier and into the malignancy.”

Jackson and colleagues also are evaluating drugs that can be used in combination with chemotherapy to ensure better passage across the blood–brain barrier.

“If there is an impermeable drug that does a great job of killing these cells, then maybe we can give an additional drug that can open the blood–brain barrier and allow the chemotherapy easy passage to the tumor,” Jackson said.

Her team at the NCI is conducting a small pilot study looking at the drug regadenoson, an adenosine receptor agonist. This work builds on a study of a bradykinin analog, Cereport, conducted in the late 1990s at the NIH and Children’s National Medical Center.

“Cereport given to rodents could open the blood–brain barrier to increase carboplatin delivery but, when the combination was given to humans, they saw no increase in OS or PFS,” Jackson said. “They thought the study failed but what they didn’t look for was how much more drug got into the brain. They just wanted to measure survival. As a result, the drug was thrown by the wayside.”

More research should focus on how much of a drug gets into the brain rather than simply assessing survival, she added.

“It may be that more of a drug gets into the brain but also comes back out because, once you open the blood–brain barrier, it may not be a one-way street,” Jackson said. “If we can monitor how much gets in and how much gets out, we might be able to gain perspective on the permeability coefficient — a box we really need to check off.”

Immunotherapies also are being evaluated for their potential to cross the blood–brain barrier in patients with melanoma, a disease in which incidence of brain metastases is “astronomical,” according to Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of hematology and oncology at St. Luke’s Cancer Center and a HemOnc Today Editorial Board member.

Sanjiv S. Agarwala, MD
Sanjiv S. Agarwala

Research by Margolin and colleagues showed ipilimumab (Yervoy, Bristol-Myers Squibb) induced similar response rates in the brain and outside the brain.

“We always thought that the brain was an immunologically privileged organ, meaning that immunotherapy would not work there,” Agarwala said during a presentation at the HemOnc Today Melanoma and Cutaneous Malignancies meeting in New York. “This is the first example of an immunotherapy working in the brain, which was a major breakthrough.”

The ongoing ABC trial is evaluating nivolumab (Opdivo, Bristol-Myers Squibb) with or without ipilimumab in patients with brain metastases. The trial includes patients who were previously untreated and asymptomatic, as well as those who were previously treated and symptomatic.

Another study has been designed to assess the anti–PD-1 therapy pembrolizumab (Keytruda, Merck) in patients with brain metastases. The preliminary results of this study have shown promising results in non–small cell lung cancer and melanoma brain metastases.

The efficacy of immunotherapy in the brain may call into question the existence of the blood–brain barrier once a cancer has metastasized.

“Breaching the blood–brain barrier is an interesting idea, but does the barrier actually exist once you have an invasive tumor?” Weber said. “Does it play an important role in excluding cells for adoptive cell therapy, for drugs, for antibodies, etc, that’s not breached by the presence of a tumor? It’s not 100% obvious that there is an intact barrier in someone with metastatic cancer.”

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Still, these data suggest that there is a new paradigm evolving for brain metastases, an area for which researchers had always tended to give up hope, Agarwala said.

“Responses you are getting outside of the brain, you may be able to reproduce inside the brain,” Agarwala said. “What this is telling us, overall, is that maybe the brain is becoming just another organ.” – by Kristie L. Kahl and Anthony SanFilippo

References:

ABTA document (stats). Available at: www.abta.org/secure/metastatic-brain-tumor.pdf. Accessed July 5, 2016.

Bellavance M-A, et al. APPS J. 2008;doi:10.1208/s12248-008-9018-7.

Carpentier A, et al. Sci Transl Med. 2016;doi:10.1126/scitransmed.aaf6086.

Grabrucker AM, et al. Curr Top Med Chem. 2013;doi:10.1007/7355_2013_22.

Groves MD, et al. Abstract 2027. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Healy AT and Vogelbaum MA. Surg Neurol Int. 2015;doi:10.4103/2152-7806.151337.

Jain KK. Nanomedicine. 2012;7:1225-1233.

Leuthardt EC, et al. PLoS ONE. 2016;doi:10.1371/journal.pone.0148613.

Long GV, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70431-X.

Margolin K, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70090-6.

Nussbaum ES, et al. Cancer. 1996;78:1781-1788.

Pardridge W. NeuroRx. 2005;doi:10.1602/neurorx.2.1.3.

Reardon DA, et al. Abstract 2009. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Watkins S, et al. Nat Commun. 2014;doi:10.1038/ncomms5196.

For more information:

Sanjiv S. Agarwala, MD, can be reached at ssagarwala0501@gmail.com.

Manmeet Ahluwalia, MD, FACP, can be reached at ahluwam@ccf.org.

James R. Connor, PhD, can be reached at jconnor@hmc.psu.edu.

Kullervo Hynynen, PhD, can be reached at khynynen@sri.utoronto.ca.

Sadhana Jackson, MD, can be reached at sadhana.jackson@nih.gov.

Todd Mainprize, MD, FRCPC, can be reached at todd.mainprize@sunnybrook.ca.

Jeffrey S. Weber, MD, PhD, can be reached at jeffrey.weber2@nyumc.org.

Disclosure: Agarwala, Ahluwalia, Connor, Hynynen, Jackson, Mainprize and Weber report no relevant financial disclosures.

 

POINTCOUNTER

Should breaching the blood–brain barrier remain a research priority in light of advances in immunotherapy?

POINT

Breaching the blood–brain barrier may not be as important for cellular immunotherapy, but it is for drugs. Consequently, it needs to remain a research priority.

Immune cells can get into the brain, but if you are giving drugs that have antibodies like the checkpoint blockers, then the blood–brain barrier can be a problem.

Rakesh K. Jain, PhD
Rakesh K. Jain

In glioblastoma, for decades, very little has happened in terms of improving OS. The only recent development is the tumor treating fields device (Optune, Novocure), a device that people have to wear on their heads every day that improves survival. Further, bevacizumab (Avastin, Genentech) — which a lot of people were putting their hopes on — did not improve OS in randomized phase 3 trials.

A hallmark of glioblastoma is leaky blood vessels. If you have leaky vessels, then drug delivery should not be a problem. But when a number of these cancer cells take over the normal blood vessels, and if these vessels still have an intact blood–brain barrier, unfortunately recurrent growth occurs around these co-opted vessels.

This is where finding a way to break down the blood–brain barrier would help — not in the primary tumor, but in these lesions that are around the normal vessels. Those are the areas where vessels do not leak, and yet those are the regions where cancer cells can grow and ultimately lead to death.

In those areas, it would be good to know how to get past the blood–brain barrier, especially with the checkpoint blockers. However, for therapies such as vaccines — which are injected directly into the brain, where you are relying on immune cells — it is a different process.

There are two kinds of immunotherapies. The one that is cell based is fine. With the other, you need a drug or an antibody to penetrate the brain. The latter is where you need to worry about the blood–brain barrier, and that is the area where research needs to remain an important priority.

Rakesh K. Jain, PhD, is Andrew Werk Cook professor of tumor biology at Harvard Medical School and director of E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital. He can be reached at rjain@mgh.harvard.edu. Disclosure: Jain reports no relevant financial disclosures.

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COUNTER

The landscape for research must change, and immunotherapy must be on the forefront.

A major therapeutic hurdle for glioblastoma has been the remarkable molecular heterogeneity within tumors. It is not surprising that cytotoxic chemotherapy has achieved only limited benefit, and targeted agents — even in combination — have failed to dramatically impact tumor control.

Douglas E. Ney, MD
Douglas E. Ney

It has long been felt that harnessing a person’s own immune system may be key to fighting cancer. Indeed, this is proving to be true. Over the past several years, advances in the understanding and development of immunological therapies have resulted in remarkable outcomes and have become the most exciting area in oncology today.

Drugs targeting the cytotoxic T-lymphocyte–associated protein 4 (CTLA4) and the programmed cell death protein 1/programmed death-ligand protein (PD-1/PD-L1) have resulted in unprecedented survival benefits and dramatic clinical responses against a range of cancer types.

These checkpoint inhibitors have resulted in long-term survival for patients with metastatic melanoma, a deadly and typically treatment refractory disease, not unlike glioblastoma. Similar immunotherapies may benefit patients with brain tumors, as tumors like glioblastoma are highly immuno-active and frequently have high PD-1 expression. Trials involving checkpoint inhibitors in patients with glioblastoma are ongoing and the results are eagerly awaited.

Recent results of the ReACT study confirm enthusiasm for immunotherapeutic therapies. In this study, 70 patients with glioblastoma at first or second recurrence received either bevacizumab plus placebo, or bevacizumab plus the EGFRvIII vaccine rindopepimut (Celldex Therapeutics). In this double blind, randomized, placebo-controlled study, patients who received rindopepimut achieved a significantly longer OS (11.3 months vs. 9.3 months; HR = 0.53, P = .0137). Further, prolonged and durable responses were seen in the rindopepimut-treated group, with 24-month OS rates of 25% in that group vs. 0% in patients who received bevacizumab plus placebo. Notably, this is the first randomized clinical trial to demonstrate a survival benefit in patients with glioblastoma using immunotherapy.

ICT-107 (ImmunoCellular Therapeutics) is an autologous dendritic cell vaccine that targets six different glioblastoma-associated antigens. Results of a phase 2 trial showed that PFS was improved by 2 months in patients who received ICT-107 (P = 0.006) compared with patients who received a matched control vaccine. Perhaps more intriguingly, in a subset of patients who were HLA-A2 positive and MGMT methylated, PFS was significantly improved (24.1 vs. 8.5 months; HR = 0.26; P = .005). Data were too immature (with median follow-up of approximately 16 months) at the time of reporting to determine if a survival benefit was achieved. These results have led to a new and ongoing randomized phase 3 trial that should shed light on the benefit of this therapy.

Numerous other immunologic trials are ongoing, and they represent the future of the field of neuro-oncology. Glioblastoma is an incredibly complex and difficult disease, and it will require a multidisciplinary effort to achieve tangible success, but we are ever closer. Immunological therapies need to remain at the forefront of neuro-oncology research. We have made tremendous gains, with even further strides to go, and it is clear that our efforts need to concentrate on this new area where we are just starting to see success.

References:

Reardon DA, et al. Neuro Oncol. 2015;doi:10.1093/neuonc/nov178.

Reardon DA, et al. Abstract IMCT-08. Presented at: Society for Neuro-Oncology Annual Meeting; Nov. 19-22, 2015; San Antonio, Texas.

Wen P, et al. Abstract 2005. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Douglas E. Ney, MD, is associate professor in the department of neurology at University of Colorado School of Medicine. He can be reached at douglas.ney@ucdenver.edu. Disclosure: Ney reports no relevant financial disclosures.