Abstract
Background.
Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for central nervous system (CNS) tumors like diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). Unlike systemic administration, locoregional CAR T therapy may result in tumor inflammation-associated neurotoxicity (TIAN), which was recently defined. This study retrospectively applies TIAN criteria to patients with DIPG/pontine DMG treated with intraventricular B7-H3 CAR T cells in the BrainChild-03 (BC-03) trial (NCT04185038).
Methods.
A retrospective analysis of DIPG/pontine DMG patients treated with locoregional B7-H3 CAR T cells in BC-03 was conducted. Neurological symptoms, headache, fever, hydrocephalus, and inflammatory markers were extracted from case reports and medical records. TIAN was classified as type 1 (mechanical damage) or type 2 (electrophysiologic dysfunction), and symptom patterns, resolution, imaging findings, and management were analyzed.
Results.
Among 21 patients (ages 2–22) receiving ≥1 infusion, 16 (76%) met TIAN criteria at least once. TIAN occurred in 49 of 152 infusions (32%), mostly grade 1 (n = 34) or grade 2 (n = 14), with one grade 3 event. Common symptoms included headache with fever (51%) and neurologic changes with headache (31%). In most patients, Type 1 vs Type 2 TIAN could not be defined; however, 1 patient required CSF diversion (type 1 TIAN), and 13 had worsening preexisting deficits (type 2). Median symptom resolution was <24 h (range: 0–33).
Conclusions.
TIAN was common within this cohort but mostly low-grade and transient. Refining its classification and understanding its clinical impact will aid safety assessments and trial comparisons for CNS-directed CAR T therapies.
Keywords: CAR-T therapy, immunotherapy, neuro-toxicity, pediatric, tumor-inflammation associated neuro-toxicity
The systemic toxicities associated with chimeric antigen receptor (CAR)T cells for treatment of hematologic malignancies (e.g., cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)1) have not been consistently observed following CAR T cell treatment of central nervous system (CNS) tumors.2 Instead, local inflammation and neural dysfunction are typically observed following cellular immunotherapy for CNS tumors, which suggests that an alternative pathophysiology may be occurring.
Recent therapeutic advances within pediatric CNS tumors have involved cellular immunotherapies, including CAR T cell therapy, explored through early phase clinical trials as a potential therapeutic approach for high-grade CNS tumors.3-7 Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are CNS tumors included within these trials as they have no known curative therapies.8-10 In addition to not having curative therapeutic options, DIPG and DMG also develop in critical midline structures within the CNS, posing a high risk for symptomatic pseudoprogression and/or neural dysfunction in the setting of immunotherapy.
Several research groups are actively investigating the use of cellular immunotherapy for DIPG and DMG, through which we are gaining a foundational experience of associated neurological toxicity. We recently conducted a phase 1 trial utilizing locoregional treatment of B7-H3-targeting CAR T cells (B7-H3 CAR T cells) in children with DIPG or pontine DMG.11 Toxicity was evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) and specific criteria for CRS and ICANs, although neither were observed. Others have similarly reported Phase 1 results administering CAR T cells to pediatric and young adult patients with DIPG/DMG or other CNS tumors, including Stanford University’s GD2-targeting CAR T cell trial (NCT04196413) and City of Hope’s IL-13ra2-zetakine CAR T cell trial (NCT04510051).3,7,12,13 Furthermore, there are also ongoing trials at Baylor College of Medicine using GD2 targeting CAR T cells (NCT04099797) and St Jude Children’s Research Hospital using B7-H3 targeting CAR T cells (NCT5835687) for children and young adults with CNS tumors. Consistent with the Seattle Children’s B7-H3 experience, and distinct from trials using systemic administration of CAR T cells, ICANS has not been described when locoregional CAR T cells are administered into the CNS ventricular CSF space.
As an alternative to capturing neural dysfunction by CTCAE, Mahdi et. al described a unique clinical syndrome of neurotoxicity observed following immunotherapy for CNS tumors, which was named tumor inflammation-associated neurotoxicity (TIAN).2 This syndrome integrates radiographic findings and clinical symptoms of pseudoprogression within a broader inflammation-induced clinical constellation, including neurologic symptoms for patients receiving immunotherapies.2 This report described 2 types of TIAN: Type 1, related to mechanical damage to the CNS, and Type 2, related to electrophysiologic-induced neurological dysfunction.2
Given the evolving understanding of TIAN and the range of neurologic symptoms observed on CNS cellular therapy trials, we aimed to describe the incidence of TIAN in patients treated on BrainChild-03 (BC-03, NCT04185038). This analysis was limited to those patients with DIPG/pontine DMG to allow consistency within tumor group and location and at the time of this analysis, the trial primary objectives have been published for this study arm. We hypothesized that TIAN would provide a unifying description of the constellation of symptoms associated with locoregional CAR T infusions, which would more accurately be attributed to CAR T therapy rather than using individual neurological symptom categories according to the NCI CTCAE.
Methods
This retrospective study analysis was approved by the Seattle Children’s Hospital Institutional Research Board (STUDY00001659). The objective of this study was to diagnose TIAN retrospectively using published criteria in a cohort of patients with DIPG treated with locoregional CAR T cell therapy enrolled onto BrainChild-03 (NCT04185038). BrainChild-03 was a phase 1 clinical trial evaluating the safety and feasibility of repetitive locoregional B7-H3 CAR T cell administration to patients with recurrent/refractory CNS tumors and DIPG. Arm C of this trial enrolled patients with DIPG, all of whom were dosed intracerebroventricularly (ICV). Metastatic disease was not excluded, while re-irradiation on trial was not allowed.
The treatment schema has been published.11 In brief, patients with radiographic diagnosis of DIPG or biopsyproven DMG of the pons received ICV B7-H3 CAR T cells every other week following a planned intra-patient dose escalation. The dose limiting toxicity (DLT) observation period for this trial included Course 1 and Course 2 (8 weeks in total). Following the first 2 courses (4 total CAR T cell infusions), subjects were eligible for further dosing every 2–4 weeks. Adverse events (AEs) were recorded twice per week during the DLT period and pre- and postinfusion with subsequent courses. CNS imaging using MRI brain and spine was completed prior to the first CAR T infusion and then every 2 months thereafter unless clinically indicated to complete sooner.
Data Collection and Analysis
On this trial,11 AE monitoring occurred at scheduled clinical visits twice weekly throughout the DLT observation period. All toxicity was graded using NCI CTCAE v.5.0. Case report forms (CRF) for this trial captured all AEs regardless of relatedness to the investigational agent. For this retrospective analysis clinical data were collected from the study CRFs and additionally from the patient’s electronic medical records with emphasis on capturing all events relevant to TIAN for patients treated on this clinical trial. Data collection specifically included headache, fever, new or worsening neurologic changes, signs and symptoms of increased intracranial pressure (ICP), or hydrocephalus, inflammatory markers in serum and CSF, and management of trial AEs, including medical management, need for hospitalization, and neurosurgical intervention. Time to resolution of symptoms was captured via eCRF and confirmed via chart review. Data was collected for all CAR T cell infusions or up to 10 months of CAR T cell infusions for those subjects who received protocol therapy for longer than 10 months.
For each subject, the central features of TIAN (including headache, fever, neurologic changes, hydrocephalus) were collected and then graded using the criteria defined by Mahdi et al (Supplementary Table 1).12 TIAN was defined as having either headache with fever, headache and neurologic change, headache, fever and neurologic change or a worsening of existing or new neurologic AE following a CAR T infusion. Type 1 TIAN was assigned if there was evidence of increased intracranial pressure. Based on the available data, those subjects who had worsening of preexisting neurologic changes while meeting criteria for TIAN were defined as having type 2 TIAN. Individual symptoms were determined to be possibly, probably or definitely related to CAR T cell infusions in all instances of TIAN. The presence of TIAN was described at each study time point using the TIAN criteria for each patient. Onset of TIAN and time to resolution, imaging and investigations completed, management and need for hospitalization were analyzed descriptively.
Results
Twenty-one patients enrolled on BC-03 Arm C (age: 2–22 years) who received at least one dose of B7-H3 CAR T cells were included in this analysis. Subject demographics for this cohort of patients are published.11 Sixteen patients received all four planned doses in the DLT period, 1 patient received 3 doses, 1 patient received 2 doses, and 3 patients received 1 dose.
Using protocol-defined criteria for AEs (CTCAE V5.0), we observed neurologic, ophthalmologic, gastrointestinal, constitutional, respiratory, cardiovascular, musculoskeletal, urinary, dermatologic, and hematologic toxicities.11 The most common toxicities during the DLT period were headache (81%), fatigue (62%) and fever (57%). Subjects also experienced nausea/vomiting (62%) and transient neurologic changes, either with worsening of existing neurologic deficits or new neurologic findings after some infusions.
TIAN Diagnosis
On review of the AEs, 16 of 21 subjects met criteria for TIAN at least once (76%). Of the 152 infusions reviewed, TIAN was observed following 49 (32%) infusions (Grade 1: n = 34, Grade 2: n = 14, Grade 3: n = 1). Of observed TIAN, symptoms included headache with fever (25/49), neurologic changes with headache (15/49), neurologic changes with headache and fever (6/49), and neurologic changes without fever (3/49). One patient required CSF diversion while meeting criteria for TIAN, most consistent with type 1 TIAN. Thirteen instances of TIAN included worsening neurologic symptoms from baseline and as such, they are most consistent with the published definition of type 2 TIAN. TIAN type could not be defined within the remainder of the TIAN instances as there was insufficient data to make this determination. Neurologic changes observed included focal weakness (N = 10), cranial nerve palsies (N = 9), ataxia (N = 8), dysphagia (N = 3), paresthesias (N = 2), and memory impairment (N = 1). Symptomatic increased ICP requiring intervention was identified in one subject within this cohort, determined retrospectively to be most consistent with Type 1 TIAN. TIAN temporal mapping of symptoms demonstrated a peak in TIAN within the DLT observation period (Figure 1).
Figure 1.
TIAN grading by subject over time.
There were 98 episodes of headache during these infusions of which 46 episodes (47%) met criteria for TIAN. Isolated headache occurred without meeting criteria for TIAN 53% of the time of which occurrences were considered possibly, probably or definitely related to the CAR T infusions in all but 2 instances. Fever occurred once in isolation when not concurrently meeting criteria for TIAN.
Temporal Relationship and Management
All patients who developed TIAN (n = 16) first met criteria for TIAN during course 1 or 2 of protocol therapy. Management of TIAN-associated toxicities was based on the constellation of symptoms observed with specific management directed at headaches, fevers, and neurologic changes.
Headaches.—
Headaches occurring in combination with other symptoms and meeting criteria for TIAN (n = 46) were managed using acetaminophen (100%), magnesium sulfate either intravenous of oral (56%), opioids (38%), tramadol (7%), ketorolac (2%), and ibuprofen (2%). Fourteen percent of patients were managed with more than one medical therapy. For patients with new or worsened headaches following a CAR T infusion, headaches resolved at a median of 2 days following infusion (range 0–13). Of those patients meeting criteria for TIAN, 6 received inpatient management for treatment of headache. There were an additional 4 episodes of inpatient management for headache in patients not meeting criteria for TIAN.
Fever.—
Nineteen patients (62%) who developed fever in the setting of TIAN had central lines. In the setting of fever, 20 blood cultures were drawn, and all were negative for bacterial and fungal infection, and no patient required an extended course of antibiotics. Within those patients who developed TIAN, one had serum cytokine data available. This patient developed recurrent fever 10 days following the most recent CAR T cell dose, requiring additional hospitalization and was found to have elevated IL-6 in serum, but did not require additional supportive or immunomodulatory intervention. One patient did not meet criteria for TIAN for a week following infusion but then experienced a grade 4 acute intra-tumoral hemorrhage (the only study DLT) and had a fever following the hemorrhage interpreted as related to the hemorrhage. One additional patient required 2 hospitalizations while meeting criteria for TIAN with fever and increased headache/vomiting. There were no prolonged hospitalizations (>24 h) secondary to headache or fever exclusively within this cohort of patients.
Neurologic changes.—
Neurologic changes seen in subjects who met criteria for TIAN are shown in Figure 2. Seven of 16 patients who met criteria for TIAN received dexamethasone: 5 patients received it for headache and 2 patients for acute neurologic change worsened from baseline. In one patient, this included new lethargy/confusion and in the other patient, it included worsened weakness from baseline. All 7 patients who received dexamethasone underwent imaging to rule out acute neurosurgical emergencies at the time of dexamethasone administration. All patients on this trial were empirically treated with an antiepileptic medication (levetiracetam, n = 19, 90%; other n = 2, 10%). There were no seizures within this cohort of patients at the time of meeting criteria for TIAN. No patients received immunomodulatory intervention with tocilizumab or anakinra.
Figure 2.
Neurologic changes observed in patients meeting criteria for TIAN.
Resolution and Recurrence
Median time from symptom onset to resolution was less than 24 h (range 0–33 h). In those subjects who developed TIAN in courses 1 and 2 (trial DLT observation period), 5 did not receive further infusions beyond the DLT observation period. Of those patients who received infusions past the DLT period, 7/11 (64%) developed TIAN in subsequent infusions. All but one patient who developed grade 2 or higher TIAN developed TIAN again beyond the DLT observation period. Maximum grade occurred within Course 2 in 15/16 patients and in Course 1 in 1 patient. This occurred without ongoing escalation in TIAN grade with subsequent infusions beyond Course 2 in any subjects.
Correlatives within Neuroimaging
In this trial, MRI brain and spine were completed prior to the first CAR T cell infusion and after 2 Courses of protocol therapy (i.e., 4 CAR T infusions), with additional neuroimaging as clinically indicated. Four patients had additional computed tomography (CT) of their head within 48 hours of meeting criteria for TIAN. These were completed to rule out neurosurgical emergencies and of these, 1 CT demonstrated worsened hydrocephalus, and the other 3 CTs were negative for bleed, infarct, or acute change in hydrocephalus. An example of an MRI prior to the first infusion and after the fourth infusion in a patient who developed TIAN in Courses 1 and 2 is shown in Figure 3. For most patients, we were not able to correlate symptoms of TIAN or TIAN grade with imaging, because imaging on this trial was completed prior to the first infusion and after finishing 2 courses of infusions (8 weeks). Furthermore, in most cases where postinfusion symptoms presented, additional acute imaging was not felt to be clinically indicated. Due to the timing of protocol-prescribed imaging before the first infusion and after 2 Courses of infusions, we were not able to correlate symptoms of TIAN or TIAN grade with imaging.
Figure 3.
MR and CT images of patient X before (A and B), after the first course (C), and after the second course (D–F) of CAR-T cell therapy. Axial FLAIR image (A) from before CAR T cell therapy demonstrates infiltrative DMG (arrows) with mild effacement of the adjacent fourth ventricle. Axial ADC map (B) demonstrates moderately cellular neoplasm (arrows), with ADC mean ± 1 SD of 943 ± 28 10−6mm2/s. Axial CT image (C) from after the first course of CAR T cell therapy demonstrates mildly prominent lateral ventricles (arrows) with Ommaya and ventricular catheter (arrowhead) in the frontal horn of the right lateral ventricle. Axial FLAIR image (D) from after the second course of CAR T cell therapy demonstrates increased tumor bulk and effacement of the adjacent fourth ventricle, with increased FLAIR hyperintensity in the tumor (arrows). Axial ADC map (E) demonstrates increased signal within the tumor (arrows), with ADC mean ± 1 SD of 1100 ± 105 10−6 mm2/s, suggesting on-target inflammation and vasogenic edema rather than tumor growth. Axial CT image (F) demonstrates increased ventriculomegaly of the lateral ventricles with new periventricular interstitial edema (arrows), suggesting acute obstructive hydrocephalus related to tumor swelling and aqueductal effacement. Ventricular catheter (arrowhead) again noted.
Discussion
Here, we demonstrate the retrospective application of the published TIAN criteria within a cohort of patients with DIPG/pontine DMG who received repeat dosing with ICV B7-H3 CAR T cells. TIAN is a neurotoxicity syndrome, distinct from ICANS that has been described following systemic CAR T cell therapy. Whereas ICANS is related to systemic CRS,1 TIAN is thought to be a localized treatment effect within CNS tumors.12 The identification of TIAN as a unique entity specific to immunotherapy in CNS tumors is a key step in understanding the toxicity of these therapies, providing a practical advantage for assessing toxicity across comparable clinical trials, and determining optimal supportive care.
On this trial, TIAN provided a unifying diagnosis for approximately half of infusions in patients who experienced headaches possibly, probably or definitely related to the CAR T cell infusion. TIAN was associated with about half of the patients who experienced headache related to CAR T cell infusions. Headache was also the most common reason for hospitalization in those patients with TIAN. TIAN captured 60% of instances requiring hospitalization/intervention through the study cohort DLT period, with 40% of patients requiring hospitalization for symptom management not meeting criteria for TIAN.
Overall, TIAN was identified in over 3-quarters of subjects who received CAR T cell infusions on one or more occasions and in one-third of total infusions reviewed. The majority of TIAN in this cohort was grade 1, with a small number of patients having episodes of grade 2 TIAN and a single patient meeting criteria for grade 3 TIAN. The highest intensity of TIAN was at completion of the DLT period (8 weeks and 4 doses of CAR T cell), concurrent with the highest dose of CAR T cell received by each patient. This finding suggests there may be cumulative neurotoxicity from repeated infusions, either related to CAR T cells present from the previous infusion or due to an accumulation of immune infiltration into the tumor. Importantly, TIAN did not persist with subsequent CAR T cell infusions, perhaps due to less frequent dosing of CAR T cells in later courses of therapy on this trial, or possibly because these CAR T cells have limited persistence.
Variability amongst trials is expected considering not only the different targeted antigens but also distinct co-signaling domains, other engineering enhancements, manufacturing strategies, dosing regimens, incorporation of lymphodepletion into the trial protocol, and biology of the underlying disease. It is also important to note that the TIAN criteria described by Mahdi et al have not yet been prospectively validated, which is a limitation in incorporating them in analyses like this. Our findings have temporal and grade differences from a previously reported GD2-targeting trial on which patients were more likely to require hospitalization and experience grade 3 or higher TIAN.13 Ongoing and future clinical trials targeting the same antigen—and also broadening the arsenal of targets—will be invaluable to begin to understand what components of cellular therapy targeting are most closely related with TIAN toxicity and the correlations with potential efficacy.
These data must be interpreted in the context of a retrospective review. One clear limitation with this cohort was that we were not able to discern type 1 TIAN from type 2 TIAN in most instances. A portion of these episodes of TIAN included neurologic changes that worsened from baseline, which are likely most consistent with type 2 TIAN. A single episode of TIAN was associated with requiring CSF diversion and may be most consistent with type 1 TIAN. Within the remainder of the TIAN episodes, we were not able to confidently draw conclusions in the differences between these 2 types of TIAN within this cohort. The definitions of TIAN subtypes are challenging to evaluate, especially retrospectively, and we were not able to describe clinically relevant subgroups. While the preclinical data support the provision of these 2 types of TIAN, there are practical challenges in adopting this within the clinical setting. Specifically, Mahdi et al describe both inflammation-induced mechanical mechanisms and inflammation-induced electrophysiological mechanisms in neurotoxicity, which in the future could potentially be distinguished in patients thanks to the rapidly advancing science of neuronal-tumoral signaling.14 In the current cohort, we were limited by clinical AE data and patient history and management in the chart and as such, were not able to delineate electrophysiologic from mechanical changes as the cause of neurotoxicity in most cases. It is often challenging to distinguish TIAN from true progression when neurologic changes occur and in general, the timing of the symptoms is the most informative. In CNS lymphoma, TIAN typically arises soon after CAR T infusion, while progression-related symptoms emerge later—a pattern likely similar in DIPG, though data are lacking. Another limitation is the lack of time-matched neuroimaging. As TIAN was often clinically mild and managed as an outpatient, neuroimaging was not regularly obtained during TIAN episodes. Furthermore, in this trial, imaging was completed approximately every 2 months, and in retrospect, these images were several weeks to months after the transient symptoms of TIAN to correlate. We did attempt to evaluate this within the manuscript, and while we did see some changes in T2 and fluid attenuated inversion recovery (FLAIR) in some patients in retrospect (Figure 2) when comparing the pre-infusion and post DLT period MRIs, this change reflects 8 weeks and 4 CAR T cell infusions in most patients. While TIAN has been described previously to be associated with radiographic changes, these were not consistently seen in this cohort, likely due to both the limited data defining neuroimaging interpretation with immune therapies15 and due to the lack of frequent imaging data in this particular cohort. It will be important to evaluate TIAN prospectively together with imaging to delineate this in future clinical trials. Despite these limitations, this analysis provides proof of principle and demonstrates the presence of TIAN, diagnosed retrospectively in a cohort of patients with DIPG treated with CAR T cell therapy on a clinical trial.
Conclusions
Here, we demonstrate that TIAN criteria can be applied to characterize neurotoxicity seen in patients with CNS tumors treated with CAR T cell therapy. While not all AEs requiring hospitalization/intervention met criteria for TIAN, the majority did. Additional information regarding optimal application of the TIAN definition and management of this syndrome should be gathered through prospective evaluation within future trials. These data underscore the importance of collaborative work in describing a practical definition of TIAN to understand toxicity related to novel therapies that are applicable across multiple trials.
Supplementary Material
Supplementary material is available online at Neuro-Oncology Practice (https://academic.oup.com/nop/).
Key Points.
Tumor inflammation-associated neurotoxicity (TIAN) is a novel entity recently described within patients treated with immunotherapy for CNS tumors.
Within this cohort, we show proof of principle in describing TIAN retrospectively in patients treated with B7H3 targeting CAR T cell therapy with DIPG and DMG.
Importance of the Study.
This study provides a critical advancement in understanding tumor inflammation-associated neurotoxicity (TIAN) in patients with DIPG and pontine DMG receiving locoregional B7-H3 CAR T cell therapy. Unlike systemic CAR T cell-associated toxicities such as ICANS, TIAN represents a distinct neurotoxicity syndrome, and its classification remains an evolving field. By retrospectively applying standardized TIAN criteria, our findings offer a framework for identifying and characterizing this toxicity, supporting improved safety assessments across CNS-directed CAR T cell trials. These data enhance our understanding of TIAN’s clinical manifestations, frequency, and resolution, reinforcing the need for standardized toxicity monitoring in locoregional CAR T therapies. Future implications include optimizing treatment protocols, minimizing toxicity, and informing the design of next-generation cellular therapies to enhance both safety and efficacy for patients with CNS tumors.
Acknowledgments
We thank the children and families who place their trust in Seattle Children’s for their care. We thank our clinical research team, including A. Thomsen, H. Ullom, S. Aravala, S. Bakotich, S. Bagchi, C. Brown, D. Chen, K. Fernandez, M. Fogg, V. Hanner, C. Krein, M. MacQuivey, Z. Maino, M. Mankowski, M. Malone, L. McCann, D. Palmer, and R. Perona. We thank our brain tumor program, including E. Crotty, D. Runco, A. Sato, A. Olsen, S. Morgan, W. Iwata, V. Klein, Z. Reinke, E. Estes, A. Breedt, C. Henson, and J. Stevens. We thank our apheresis team, the Investigational Drug Service team, the Therapeutic Cell Production Core, and Seattle Children’s Therapeutics’ Correlative Sciences Lab.
Footnotes
Conflict of interest statement: N.A.V. holds equity in and serves as the Scientific Advisory Board Chair for BrainChild Bio, Inc. R.A.G. is an inventor and receives royalties on patents related to CAR T cell technologies that are licensed to Juno Therapeutics, a Bristol Myers Squibb company, and serves as a consultant to Moonlight Bio. M.C.J. holds equity in and is the Chief Scientific Officer of BrainChild Bio, Inc. M.C.J. holds equity in, serves as a member of the Joint Steering Committee, and is a Board Observer for Umoja Biopharma, Inc. N.A.V., J.R.P., and M.C.J. are inventors on issued and pending patents related to CAR T cell therapies. All other authors declare no competing interests.
Data Availability
Data from this project are available upon request.
References
- 1.Gardner RA, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134(24):2149–2158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ronsley R, Bertrand KC, Song EZ, et al. CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials. Cancer Metastasis Rev. 2024;43(4):1205–1216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022;603(7903):934–941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Monje M, Mahdi J, Majzner R, et al. Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas. medRxiv. 2024. [Google Scholar]
- 5.Vitanza NA, Wilson AL, Huang W, et al. Intraventricular B7-H3 CAR T cells for diffuse intrinsic pontine glioma: preliminary first-in-human bioactivity and safety. Cancer discovery. 2023;13(1):114–131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Brown CE, Hibbard JC, Alizadeh D, et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. 2024;30(4):1001–1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wang L, Oill AT, Blanchard M, et al. Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R 2-targeting CAR T cells: an interim analysis. Res Sq. 2023. [Google Scholar]
- 8.Veldhuijzen van Zanten SEM, Baugh J, Chaney B, et al. ; members of the SIOPE DIPG Network. Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease. J Neurooncol. 2017;132(2):255–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Baugh J, Bartels U, Leach J, et al. The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease. J Neurooncol. 2017;132(2):323–331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, et al. Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries. J Clin Oncol. 2018;36(19):1963–1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vitanza NA, Ronsley R, Choe M, et al. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial. Nat Med. 2025;31(3):861–868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mahdi J, Dietrich J, Straathof K, et al. Tumor inflammation-associated neurotoxicity. Nat Med. 2023;29(4):803–810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Monje M, Mahdi J, Majzner R, et al. Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas. Nature. 2025;637(1):708–715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Venkatesh HS, Morishita W, Geraghty AC, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573(7775):539–545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lau D, Corrie PG, Gallagher FA. MRI techniques for immunotherapy monitoring. J ImmunoTher Cancer. 2022;10(9):e004708. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data from this project are available upon request.