CAR T Cell Therapy for Pediatric Brain Cancer
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Seattle Children's Hospital
Disqualifiers: Cardiac dysfunction, Immunodeficiency, Active infection, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial uses a patient's own modified immune cells to treat aggressive brain tumors in children and young adults. The immune cells are enhanced to better recognize and attack cancer cells in the brain. This approach has shown remarkable results in treating certain cancers and is now being explored for brain tumors.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, you must stop certain treatments like chemotherapy, immunotherapy, and radiotherapy before enrolling, and corticosteroid treatment must be stable or decreasing.
What data supports the effectiveness of the treatment SC-CAR4BRAIN for pediatric brain cancer?
Research shows that CAR T cell therapy, which is a type of treatment that uses modified immune cells to target cancer, has shown some positive responses in early trials for pediatric brain tumors. Additionally, targeting B7-H3, a protein found on many cancer cells, with CAR T cells has shown strong activity in preclinical studies against pediatric brain tumors.
12345What safety data exists for CAR T cell therapy in pediatric brain cancer?
In early clinical trials for CAR T cell therapy in children with brain tumors, there were no severe dose-limiting toxicities reported. Some patients experienced expected side effects like low blood cell counts and mild issues such as headaches and liver enzyme changes, but these were manageable.
12678What makes the SC-CAR4BRAIN treatment unique for pediatric brain cancer?
The SC-CAR4BRAIN treatment is unique because it uses genetically engineered T cells that target specific proteins (B7-H3, EGFR806, HER2, and IL13) found on brain tumor cells, and it can be delivered directly to the brain, potentially improving effectiveness and reducing side effects compared to traditional treatments like surgery, chemotherapy, and radiotherapy.
12379Eligibility Criteria
This trial is for children and young adults with specific brain tumors like DIPG, DMG, or recurrent/refractory CNS tumors. They must have a life expectancy of at least 8 weeks, be in good physical condition (Lansky/Karnofsky score ≥ 60), have proper organ function, agree to use contraception if applicable, and have a catheter placed for treatment delivery.Inclusion Criteria
I am between 1 and 26 years old, or between 12 and 26 for the first 3 subjects.
My brain or spinal cord disease is not responding to treatment and there are no standard treatments left.
I have recovered from the side effects of my previous cancer treatments.
+10 more
Exclusion Criteria
I am currently suffering from a severe infection.
Unwilling to provide consent/assent for study participation
I have a condition that affects my immune system or bone marrow.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive SC-CAR4BRAIN infusions via an indwelling catheter into the ventricular system
14 weeks
Multiple visits for infusion and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Extension
Participants may continue to receive additional courses of CAR T infusions if criteria are met
Long-term
Participant Groups
The study tests SC-CAR4BRAIN therapy using the patient's own T cells engineered to target tumor cells via CARs that recognize B7-H3, EGFR806, HER2, and IL13-zetakine. The modified T cells are delivered directly into the brain through a catheter. Patients are divided into two groups based on their type of tumor.
2Treatment groups
Experimental Treatment
Group I: Arm B - DMG & recurrent/refractory tumorsExperimental Treatment1 Intervention
Group II: Arm A - DIPGExperimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Seattle Children's HospitalSeattle, WA
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Who Is Running the Clinical Trial?
Seattle Children's HospitalLead Sponsor
References
CAR-T cells for pediatric brain tumors: Present and future. [2021]Chimeric Antigen Receptor T (CAR-T) cells are currently approved for B cell malignancies only, in children and adults. Despite a lack of robust evidence to approve such cellular immunotherapy for pediatric solid tumors, there is a growing interest for this approach in the treatment of pediatric brain tumors. Following the identification of tumor antigens as targets, the first clinical trials demonstrated some degree of clinical and biological responses to CAR-T cells for such tumor types. Additionaly, several preclinical studies have recently identified new attractive targets and antigen combination strategies, along with a superior tumor trafficking following locoregional administration. We review here the preclinical and clinical knowledge at the basis of the current clinical development of CAR-T cells for pediatric brain tumors.
Advances in CAR T cell immunotherapy for paediatric brain tumours. [2022]Brain tumours are the most common solid tumour in children and the leading cause of cancer related death in children. Current treatments include surgery, chemotherapy and radiotherapy. The need for aggressive treatment means many survivors are left with permanent severe disability, physical, intellectual and social. Recent progress in immunotherapy, including genetically engineered T cells with chimeric antigen receptors (CARs) for treating cancer, may provide new avenues to improved outcomes for patients with paediatric brain cancer. In this review we discuss advances in CAR T cell immunotherapy, the major CAR T cell targets that are in clinical and pre-clinical development with a focus on paediatric brain tumours, the paediatric brain tumour microenvironment and strategies used to improve CAR T cell therapy for paediatric tumours.
Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery. [2023]Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells.
Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors. [2022]Intracranial delivery of HER2-targeting CAR-T cells was well tolerated in 3 patients with CNS tumors.
CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. [2021]Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.
CAR T Cell Therapy's Potential for Pediatric Brain Tumors. [2021]Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood-brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells' efficiency and safety in the field of pediatric neuro-oncology.
The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors. [2022]Adoptive cell therapy with genetically modified T cells holds the promise to improve outcomes for children with recurrent/refractory solid tumors and has the potential to reduce treatment complications for all patients. Although T cells that express chimeric antigen receptors (CARs) specific for CD19 have had remarkable success for B-cell-derived malignancies, which has led to their approval by the U.S. Food and Drug Administration, CAR T cells have been less effective for solid tumors and brain tumors. Lack of efficacy is most likely multifactorial, but heterogeneous antigen expression; limited migration of T cells to tumor sites; and the immunosuppressive, hostile tumor microenvironment have emerged as major roadblocks that must be addressed. In this review, we summarize the clinical experience with CAR T-cell therapy for pediatric solid tumors, including brain tumors. In addition, we review strategies that have been and are being developed to enhance their antitumor activity.
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. [2023]Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8+ T cells in the cerebrospinal fluid (CSF) over time. Additionally, of the five patients evaluable for disease response, three experienced transient radiographic and/or clinical benefit not meeting protocol criteria for response. The first three patients received CAR T cells alone; later patients received lymphodepletion before the first infusion. There were no dose limiting toxicities (DLTs). Aside from expected cytopenias in patients receiving lymphodepletion, serious adverse events possibly attributed to CAR T cell infusion were limited to one episode of headache and one of liver enzyme elevation. One patient withdrew from treatment during the DLT period due to a Grade 3 catheter-related infection and was not evaluable for disease response, although this was not attributed to CAR T cell infusion. Importantly, scRNA- and scTCR-sequence analyses provided insights into CAR T cell interaction with the endogenous immune system. In particular, clonally expanded endogenous CAR- T cells were recovered from the CSF, but not the peripheral blood, of patients who received intraventricular IL13BBζ-CAR T cell therapy. Additionally, although immune infiltrates in CSF and post-therapy tumor did not generally correlate, a fraction of expanded T cell receptors (TCRs) was seen to overlap between CSF and tumor. This has important implications for what samples are collected on these trials and how they are analyzed. These initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children with brain tumors.
Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. [2022]Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.