Novel approaches to malignant brain tumor treatment aim to overcome familiar challenges
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Although therapeutic advances during the past decade have dramatically improved cancer outcomes overall, the outlook for patients with malignant brain tumors has remained poor.
The 5-year relative survival rate for these patients increased only from 23% between 1975 and 1977 to 36% between 2009 and 2015, with rates in the single digits for those with particularly lethal brain tumor types, according to an analysis of population-based registry data by Miller and colleagues.
Source: University of California, Irvine.
One challenge to treatment of these aggressive tumors has been the inability of drugs to penetrate the blood-brain barrier. Use of treatments that can cross the barrier, such as chemotherapy and radiation therapy, often is limited because of toxicity. Other standard treatments, such as surgery, are not even an option for some patients because of the tumor location.
“Achieving effective treatment with minimal side effects is the biggest challenge in the field of malignant brain tumors right now,” Daniela A. Bota, MD, PhD, professor of neurology, vice dean for clinical research and medical director of the comprehensive brain tumor program at University of California, Irvine, told Healio | HemOnc Today. “Yet, we are making progress in glioblastoma. We are understanding more and more about what we need to do to develop more effective treatments, and it is my sincere belief that the next few years will bring us closer to a potential cure.”
Healio | HemOnc Today spoke with neuro-oncologists and radiation oncologists about novel treatment approaches for malignant brain tumors that have shown promise among adults and children, vaccines and other advances on the horizon, and efforts to address ongoing challenges facing this patient population.
Glioblastoma: ‘A complex disease’
Glioblastoma remains the most common and most lethal type of brain cancer in the United States, as well as one of the most difficult types to treat.
“Glioblastoma is a tumor that, until now, has been resistant to immunotherapy,” Bota said. “We have tried checkpoint inhibitors, which are revolutionizing the world of cancer for so many other malignancies, but unfortunately for both newly diagnosed and recurrent glioblastoma, the addition of checkpoint inhibitors to standard of care has not given us positive results.”
Some studies have suggested that administering checkpoint inhibitors before surgery for recurrent glioblastoma could improve survival outcomes.
Cloughesy and colleagues examined whether neoadjuvant vs. adjuvant-only treatment with the PD-1 inhibitor pembrolizumab (Keytruda, Merck) could alter the functional immune landscape and improve survival among 35 adults with recurrent, resectable glioblastoma.
Results of the study, published in 2019 in Nature Medicine, showed neoadjuvant pembrolizumab led to a significant increase in OS compared with adjuvant pembrolizumab (13.7 months vs. 7.5 months; HR = 0.39; 95% CI, 0.17-0.94). Neoadjuvant therapy also appeared associated with longer PFS (3.3 months vs. 2.4 months; HR = 0.43; 95% CI, 0.2-0.9). However, researchers noted the study’s small sample size and the need for larger trials to confirm their findings.
“We are still learning about which avenues will be our ‘success stories’ for patients with malignant brain tumors,” Rupesh R. Kotecha, MD, radiation oncologist and chief of radiosurgery and director of central nervous system metastasis at Miami Cancer Institute, part of Baptist Health South Florida, told Healio | HemOnc Today. “For immunotherapy, the studies so far have not recapitulated those in other disease sites where we have seen significant advances and improvements in survival. The studies performed to date have not been revealing and therefore we are not certain whether this is because of a failure of a particular treatment regimen, if the tumor biology is resistant to the type of immunotherapy approaches being tested, or if we are selecting the right patient population for testing of these therapies.”
One ongoing randomized clinical trial is examining the use of combination immunotherapy among an international cohort of patients with glioblastoma.
“This study includes patients with newly diagnosed MGMT-unmethylated glioblastoma and is testing two immunotherapy agents, nivolumab [Opdivo, Bristol Myers Squibb] plus ipilimumab [Yervoy, Bristol Myers Squibb], compared with standard-of-care temozolomide, which has been used in these patients for years but from which they do not benefit significantly with regard to survival,” Kotecha said.
Other research has shown administration of temozolomide at different times in a day may lead to different outcomes.
Results of a study published in 2021 in Neuro-Oncology Advances showed an association of morning administration of temozolomide with longer OS compared with evening administration among a cohort of patients with newly diagnosed glioblastoma. Of note, the benefit appeared more pronounced among patients with methylated MGMT disease.
“Glioblastoma is a complex disease and we simply need better treatments for these patients, which is why I devote all of my time and research to them,” Jian Li Campian, MD, PhD, associate professor of oncology in the department of oncology at Mayo Clinic in Rochester, Minnesota, and an author of the temozolomide study, told Healio | HemOnc Today. “But targeting one aspect is not enough to change the entire course of the disease — we need combination therapies. Finding a way to improve patients’ own immune status, such as correcting tumor- and treatment-related lymphopenia by cytokines, with combination therapies such as checkpoint inhibitors, vaccines or chimeric antigen receptor T-cell therapy, is something that should be tested. We are conducting this research now in [glioblastoma] animal models.”
Pediatric brain tumors
Pediatric brain tumors present their own set of challenges, depending on the type of tumor. Low-grade or benign tumors can be cured with surgery, whereas aggressive, inoperable malignant tumors typically result in short OS despite best treatments.
“Several advancements are on the horizon for pediatric patients with brain tumors and as we understand the molecular drivers of these tumors better, we will be able to uncover potential targets for those drivers,” Eric M. Thompson, MD, pediatric neurosurgeon at Duke University, told Healio | HemOnc Today.
“Essentially, we are entering a world of more personalized medicine as we obtain more data about what is causing and driving these pediatric brain tumors,” Thompson said. “Immunotherapy is a promising treatment avenue for pediatric brain tumors, and other studies are looking at personalizing therapy for certain pediatric patients.”
Vaccines also appear promising.
Thompson received a $1.8 million grant through FDA’s Orphan Products Grants Program to conduct a phase 2 study of a peptide vaccine targeting cytomegalovirus antigen for treatment of newly diagnosed pediatric high-grade glioma and diffuse intrinsic pontine glioma, as well as recurrent medulloblastoma.
“Cytomegalovirus is expressed in brain tumors, such as malignant gliomas, diffuse intrinsic pontine gliomas and in medulloblastomas, but not in normal brain tissue,” Thompson said. “We think this is an interesting target because it can attack these proteins in the tumors but leave normal brain tissue alone.”
The trial is being conducted through the CONNECT Consortium, which includes some of the busiest academic medical centers throughout North America and the world, according to Thompson.
“This is an exciting grant from the FDA and is important for these pediatric tumor types that are even rarer than adult brain tumors,” he said. “It is imperative for grants like this to fund interesting trials so that we can move the needle forward for patients who have rarer tumor types.”
‘Multiantigen targeting will be key’
Although some low-grade pediatric brain tumors have specific mutations that can be efficiently targeted with a single pathway drug, the same cannot be said of high-grade pediatric brain tumors, Nicholas A. Vitanza, MD, pediatric neuro-oncologist at Seattle Children’s Hospital, told Healio | HemOnc Today.
“Most of us in the field of pediatric neuro-oncology have seen the failures of molecularly targeted therapies for aggressive brain lesions,” Vitanza said. “Even as we learn more about the disease biologically, molecularly and epigenetically, no treatments have been a silver bullet. This was part of my interest in developing the brain tumor program at Seattle Children’s Hospital.”
Vitanza and colleagues are conducting three trials at Seattle Children’s including pediatric patients with mostly fatal disease that progressed after initial standard treatment. BrainChild-01 is examining the use of locoregionally administered, HER2-directed CAR T cells; BrainChild-02 is using EGFR-specific CAR T cells to treat children and young adults with relapsed or refractory EGFR-positive central nervous system tumors; and BrainChild-03 is using B7-H3-targeted CAR T cells for all patients with recurrent CNS tumors and those with the fatal brain tumor diffuse intrinsic pontine glioma.
“In the future, multiantigen targeting will be key when treating these patients. We hope to open a study of a multiantigen CAR T-cell therapy within the next year for pediatric patients with brain tumors,” Vitanza said. “We have more of an understanding of what cytokines are necessary to get CAR T cells to the tumor and once they get to the tumor, to not exhaust. In a few years, we will be living in a world where we give a CAR T cell that can express specific cytokines so that it ‘makes its own soup’ of cytokines around the CAR T cell that enhances its function and gives the cell the best chance to get where it needs to go.”
Bota also sees potential in a multiantigen-directed approach.
She and colleagues developed the clinical strategy for a personalized cancer vaccine, AV-GBM-1 (AIVITA Biomedical), that targets multiple antigens from autologous tumor-initiating cells that contribute to rapid disease growth.
Results of a phase 2 trial showed longer PFS with the vaccine compared with historical outcomes with standard-of-care treatment among a cohort of patients with newly diagnosed glioblastoma. Patients also tolerated the vaccine well.
“For vaccines, many clinical trials have shown great safety, but efficacy is not yet known. Much of the work on dendritic cell-based antitumor vaccines is now moving toward phase 3 clinical trials,” Bota said. “We are learning from the biology of glioblastoma that many times the problem is with the ability of the body to fight this cancer type because it is not localized at one level but at multiple levels.”
Other novel vaccines and oncolytic virus therapies developed at Duke University and at Universidad de Navarra in Spain also have begun to show promise, Vitanza added.
“However, we are in the first wave of understanding what these agents do in isolation from a safety and benefit perspective,” Vitanza said. “The promise is that for most aggressive brain tumor types, cures have all come from combined therapies and we haven’t even started to see the wave of combination immunotherapy treatment yet, but when we do, that is when we will have the ability to make a difference.”
Combination therapies, catheters
Another strategy being explored is immunotherapy combined with stereotactic radiation therapy.
“This is something that is currently being tested in the extracranial space and we are now exploring this in the brain, as well,” Kotecha said. “We have an ongoing trial here at Miami Cancer Institute that we are conducting along with Memorial Sloan Kettering Cancer Center in which patients with recurrent glioblastoma are receiving nivolumab in combination with stereotactic radiation therapy with the hope that we can achieve local disease control with radiation but also help to stimulate treatment response and an overall treatment effect with immunotherapy. There is another ongoing trial looking at a similar type of concept in a national setting for patients who have recurrent glioblastoma. That trial is examining the immunotherapy agent atezolizumab [Genentech, Roche] combined with the anti-IL-6-receptor inhibitor tocilizumab and stereotactic radiotherapy.”
For pediatric brain tumors, another novel treatment approach includes use of Ommaya reservoir catheters.
“With these catheters, we can deliver a CAR T-cell therapy either directly into the ventricular fluid of the brain or directly into the tumor cavity,” Vitanza said. “This is what we have been using in some of our trials, and preliminary data showed no patient has had cytokine release syndrome. By administering the cellular therapy directly into the brain, we are not only getting the cells to the area that we want them to go but we might be mitigating one of the most dangerous toxicities of CAR T-cell therapy.”
Continued challenges
Despite the promising research efforts underway, challenges remain — including access to clinical trials for certain patients.
In a cross-sectional survey conducted by the American Brain Tumor Association as part of its Metastatic Brain Tumor Initiative and published in NeuroOncology Practice, 72% of academic and 59% of private practice physicians reported that one or more of their patients with brain metastases had been denied participation in clinical trials.
Efforts have been made to improve clinical trial eligibility.
In November 2020, the Society for Neuro-Oncology organized a think tank to review the current landscape of and prioritize areas for improvement in glioblastoma clinical trials. Experts identified potential challenges related to clinical trial eligibility criteria and offered recommendations for design of future trials.
“Survival outcomes for our patients with glioblastoma have remained stagnant and we are not happy with this as clinicians,” Kotecha said. “We work every single day to design new trial concepts that have better patient selection. We are testing newer drugs, combining radiation with those drugs, and incorporating patient-centric outcomes to improve survival for our patients. When designing these clinical trials, we must think very carefully from the beginning about patient selection, such as the tumor profile for each individual patient and whether we choose specific therapies for that patient over another patient who has that same diagnosis.”
It is also important to keep in mind that some patients with metastatic brain tumors do not want the standard-of-care therapies that have been used for so long, Kotecha added.
“We should stop enrolling those patients onto those types of studies,” he said. “We know how our patients with glioblastoma do — they have done the same this year, last year and the year before that. We should take the well-captured historical data from prior clinical trials and use it as benchmarks so that we do not continue to randomly assign patients to a certain therapy and commit them to that standard of care.”
Vitanza said more clinical trials are needed for children with brain tumors.
“The biggest challenge we face with recurrent brain tumors is the life expectancy at the time of recurrence, which is usually on the scale of months — these children do not have a lot of time. We need more trial options so that children do not have to wait on lists to get on trials,” Vitanza said. “We need to develop our cellular products more quickly so that from the time the patient enrolls in a trial and we start developing this cellular therapy, we can get it to patients faster. We also need increased partnerships where patients don’t have to travel so far for treatment. We see so many children who have already gone through so much and then we have to take them away from home for significant parts of their lives, which is another layer of heartache on top of all of their other circumstances. Having more trials open at more sites and having more sites partner with other sites is important.”
Building clinical trials with complex designs in which multiple agents can be studied also remains a challenge, Bota said.
“One of the issues with this study design is that many times different immunotherapies are produced by different companies and many of them are still experimental even for other cancer types. Collaborations between multiple industry partners will be our next step.”
Regarding immunotherapy for malignant brain tumors, Campian said research must focus on overcoming immune resistance.
“This is where immunotherapy has hope to work in glioblastoma,” Campian said. “Looking at trials like CheckMate 143, CheckMate 498 and many others, these were all negative. However, during all these trials, no one checked lymphocytes, a critical component in our immune system. How could we miss something so simple? This is the low-hanging fruit. My colleagues and I are now conducting an early-phase trial in patients with newly diagnosed high-grade gliomas with a novel long-acting recombinant human interleukin-7 analog that we have so far found to be very safe. This long-acting IL-7 analog increases lymphocyte counts; in particular, it increases both CD4 and cytotoxic CD8 cell counts.”
Thompson expressed confidence in the many skilled researchers throughout the world currently conducting studies of pediatric brain tumors, Thompson said.
“The future is promising in a lot of ways for patients with brain tumors that have previously been incurable and have had poor results,” Thompson added. “Our ultimate hope is to improve survival and quality of life for our patients with challenging brain tumors.”
- References:
- Bagley SJ, et al. Clin Cancer Res. 2021;doi:10.1158/1078-0432.CCR-21-2750.
- Bota D, et al. Abstract 319. Presented at: Society for Immunotherapy of Cancer Annual Meeting (virtual); Nov. 9-14, 2020.
- Cloughesy TF, et al. Nat Med. 2019;doi:10.1038/s41591-018-0337-7.
- Damato AR, et al. Neurooncol Adv. 2021;doi:10.1093/noajnl/vdab041.
- Kim AE, et al. Neurooncol Pract. 2021;doi:10.1093/nop/npab042.
- Miller KD, et al. CA Cancer J Clin. 2021:doi:10.3322.caac.21693.
- For more information:
- Daniela A. Bota, MD, PhD, can be reached at University of California, Irvine, 1001 Health Sciences Road, Irvine, CA 92697; email: dbota@hs.uci.edu.
- Jian Li Campian, MD, PhD, can be reached at Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: campian.jian@mayo.edu.
- Rupesh R. Kotecha, MD, can be reached at Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL 33176; email: rupeshk@baptisthealth.net.
- Eric M. Thompson, MD, can be reached at Duke University, 2301 Erwin Road, Durham, NC 27705; email: eric.thompson@duke.edu.
- Nicholas A. Vitanza, MD, can be reached at Seattle Children’s Hospital, P.O. Box 5371, Seattle, WA 98145; email: nicholas.vitanza@seattlechildrens.org.
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