The safety and accuracy of intratumoral catheter placement to infuse viral immunotherapies in children with malignant brain tumors: a multi-institutional study.
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2024-04
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Abstract
Objective
Relatively little is known about the safety and accuracy of catheter placement for oncolytic viral therapy in children with malignant brain tumors. Accordingly, this study combines data from two phase I clinical trials that employed viral immunotherapy across two institutions to describe the adverse event profile, safety, and accuracy associated with the stereotactic placement and subsequent removal of intratumoral catheters.Methods
Children with progressive/recurrent supratentorial malignant tumors were enrolled in two clinical trials (NCT03043391 and NCT02457845) and treated with either the recombinant polio:rhinovirus (lerapolturev) or the genetically modified oncolytic herpesvirus (G207). Age, sex, race, tumor diagnosis, and tumor location were analyzed. Events related to the catheter placement or removal were categorized. A catheter that was either pulled back or could not be used was defined as "misplaced." Neuronavigation software was used to analyze the accuracy of catheter placement for NCT03043391. Descriptive statistics were performed.Results
Nineteen patients were treated across the two completed trials with a total of 49 catheters. The mean ± SD (range) age was 14.1 ± 3.6 (7-19) years. All tumors were grade 3 or 4 gliomas. Nonlobar catheter tip placement included the corpus callosum, thalamus, insula, and cingulate gyrus. Six of 19 patients (31.6%) had minor hemorrhage noted on CT; however, no patients were symptomatic and/or required intervention related to these findings. One of 19 patients had a delayed CSF leak after catheter removal that required oversewing of the surgical site. No patients developed infection or a neurological deficit. In 7 patients with accuracy data, the mean ± SD distance of the planned trajectory (PT) to the catheter tip was 1.57 ± 1.6 mm, the mean angle of the PT to the catheter was 2.43° ± 2.1°, and the greatest distance of PT to the catheter in the parallel plane was 1.54 ± 1.5 mm. Three of 49 (6.1%) catheters were considered misplaced.Conclusions
Although instances of minor hemorrhage were encountered, they were clinically asymptomatic. One of 49 catheters required intervention for a CSF leak. Congruent with previous studies in the literature, the stereotactic placement of catheters in these pediatric tumor patients was accurate with approximately 95% of catheters having been adequately placed.Type
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Barkley, Ariana, Eric Butler, Christine Park, Allan Friedman, Daniel Landi, David M Ashley, Darell Bigner, Joshua D Bernstock, et al. (2024). The safety and accuracy of intratumoral catheter placement to infuse viral immunotherapies in children with malignant brain tumors: a multi-institutional study. Journal of neurosurgery. Pediatrics, 33(4). pp. 359–366. 10.3171/2023.12.peds23404 Retrieved from https://hdl.handle.net/10161/32182.
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Scholars@Duke
Allan Howard Friedman
At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage.
Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In collaboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better treatment for this condition. At present, trials of monoclonal antibodies and novel chemotherapeutic agents are being carried out.
Although physicians have been interested in seizures since the time of Hippocrates, the origin of seizures remains obscure. At Duke University we have treated approximately thirty seizure patients a year by removing abnormal portions of brain. Tissue from these resections is being analyzed for genetics and receptor abnormalities. Positron emission tomography and magnetic resonance imaging are being used to ferret out the origin of the patient's seizures.
Approximately 28,000 patients each year suffer a ruptured intracranial aneurysm. Approximately ten percent of these patients have a genetic predisposition to forming intracranial aneurysms. In conjunction with the Division of Neurology, we are screening candidate genes searching for the cause of intracranial aneurysms.
Daniel Bryce Landi
David Michael Ashley
My career in cancer research dates more than two decades. I am credentialed in both pediatric and adult neuro-oncology practice and this has been the focus of my efforts in translational research and leadership. As evident from my publication and grant support record, my primary academic focus has been on neurologic tumors, the development of innovative therapies and approaches to care. These efforts have included basic and translational laboratory research. My experience includes moving laboratory findings in brain tumor immunology and epigenetics into early phase clinical trials. I have expertise in immuno-oncology, having developed and clinically tested dendritic cell vaccines and other immuno-therapeutics. My achievements in research have led to change in practice in the care of children and adults with brain tumors, including the introduction of new standards of practice for the delivery of systemic therapy. I am highly regarded for this work, as evidenced by numerous invitations to plenary sessions and symposia of international standing. I have been the principal investigator of a number of important national and international studies, both clinical and pre-clinical. I am recognized as a senior figure and opinion leader in neuro-oncology nationally and internationally. I have held several significant leadership roles, including Director of two major cancer centers, I served as the Chair of Medicine at Deakin University, the Program Director of Cancer Services at University Hospital Barwon Health, and Executive Director of the Western Alliance Academic Health Science Centre (Australia). I began my current position as Director of The Preston Robert Tisch Brain Tumor Center, Head, Preuss Laboratory, in March 2018. In this role, I am responsible for the clinical care, research, and educational program related to Brain Tumor Center. I am also a senior investigational neuro-oncologist within the adult brain tumor program at Duke.
Darell Doty Bigner
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).
There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.
For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.
As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.
We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.
My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor and with anti-CD40, a fully human monoclonal antibody which converts tumor stimulant macrophages into tumor suppressive macrophages. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.
We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.
I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.
The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I was Principal Investigator, was funded for 30 years at which time the type of grant was discontinued. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. My last NCI Award was an Outstanding Investigator Award from 2014 to 2022.
In addition to the representative publications listed, I have made national presentations and international presentations during the past year.
My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.
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