CAR T Cell Therapy for Pediatric Brain Cancer

Overseen By Rebecca Ronsley, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Disqualifiers: Cardiac dysfunction, Immunodeficiency, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 14 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CAR T cell therapy for children and young adults with specific brain cancers, such as diffuse intrinsic pontine glioma (DIPG) and other challenging brain tumors. The treatment, SC-CAR4BRAIN, involves engineering a patient's T cells to recognize and attack cancer cells, then delivering them directly to the brain through a special tube. There are two groups: one for those with DIPG and another for those with other difficult brain tumors. Suitable candidates have already completed standard treatments for these tumors and have a special catheter placed in their brain for this therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that SC-CAR4BRAIN, a type of CAR T cell therapy, is being tested for safety in treating children's brain cancer. These CAR T cells target specific proteins on tumor cells, such as B7-H3, EGFR806, HER2, and IL13-zetakine.

Since this treatment is in the early testing stages, detailed safety information remains limited. However, early trials primarily focus on assessing safety. Although specific trial data isn't available yet, reaching this phase suggests some initial confidence in its safety.

CAR T cell therapies can sometimes cause side effects, such as cytokine release syndrome, a strong immune reaction. These effects can vary, and doctors closely monitor patients to manage any issues. Prospective trial participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for pediatric brain cancer, which often include surgery, radiation, and chemotherapy, SC-CAR4BRAIN offers a unique approach. This therapy is a type of CAR T cell treatment, which involves reprogramming the patient’s own immune cells to specifically target and destroy cancer cells. Researchers are excited about SC-CAR4BRAIN because it targets cancer cells more precisely, potentially reducing damage to healthy brain tissue and minimizing side effects. Additionally, this innovative approach could offer new hope for hard-to-treat tumors like DIPG and DMG, which are notoriously resistant to conventional therapies.

What evidence suggests that this trial's treatments could be effective for pediatric brain cancer?

Research has shown that SC-CAR4BRAIN therapy targets specific proteins on tumor cells, such as B7-H3, EGFR806, HER2, and IL13-zetakine. These proteins often appear in children's brain cancers like DIPG and DMG. In this trial, participants will join different treatment arms: Arm A for DIPG and Arm B for DMG and recurrent/refractory tumors. By focusing on these proteins, the modified T cells aim to locate and destroy cancer cells. Early evidence suggests this method could be effective because these proteins typically do not appear on healthy cells, reducing the risk of harming normal tissue. Initial results have shown promise in directly targeting brain tumors with this approach. ^{1 2 3 4 6}

Who Is on the Research Team?

Rebecca Ronsley, MD

Principal Investigator

Seattle Children's Hospital

Rebecca Ronsley, MD

Principal Investigator

Seattle Children's Hospital

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• SC-CAR4BRAIN

Trial Overview 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.

How Is the Trial Designed?

Group I: Arm B - DMG & recurrent/refractory tumors Experimental Treatment 1 Intervention

Group II: Arm A - DIPG Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Published Research Related to This Trial

Brain tumors are the most common solid tumors in children and the leading cause of cancer-related deaths, highlighting the urgent need for more effective treatments.

Recent advancements in CAR T cell immunotherapy show promise for improving outcomes in pediatric brain cancer, with ongoing research focusing on specific targets and strategies to enhance the effectiveness of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in CAR T cell immunotherapy for paediatric brain tumours. Rao, P., Furst, L., Meyran, D., et al.[2022]

In a phase I clinical trial involving six pediatric brain tumor patients, IL13BBζ-CAR T cell therapy showed promise, with three out of five evaluable patients experiencing transient benefits, although these did not meet the strict criteria for response.

The therapy was well-tolerated, with no dose-limiting toxicities reported, and serious adverse events were minimal, suggesting a favorable safety profile for this innovative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Wang, L., Oill, AT., Blanchard, M., et al.[2023]

In a study of 49 pediatric brain tumor patient-derived xenografts, B7-H3 was identified as a promising target for CAR T-cell therapy due to its high and consistent expression across various tumor types, while HLA class I expression was found in all high-grade gliomas but only in 57.1% of other tumor subtypes.

B7-H3-CAR T cells demonstrated effective tumor recognition and induced significant tumor regression in both in vitro and in vivo models, suggesting a potential survival advantage for patients with pediatric brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Haydar, D., Houke, H., Chiang, J., et al.[2023]

Adoptive cell therapy using CAR T cells has shown great success in treating B-cell malignancies, leading to FDA approval, but has faced challenges in effectively targeting pediatric solid tumors and brain tumors due to factors like varied antigen expression and a hostile tumor environment.

The review discusses ongoing strategies to improve the effectiveness of CAR T-cell therapy for solid tumors, highlighting the need to enhance T cell migration to tumor sites and overcome the immunosuppressive conditions present in these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors. DeRenzo, C., Krenciute, G., Gottschalk, S.[2022]

Atypical teratoid/rhabdoid tumors (ATRTs) express the B7-H3 protein, which is crucial for their growth and can be targeted for therapy, highlighting its potential as a therapeutic target for this aggressive pediatric cancer.

Using B7-H3-targeted CAR T cells delivered directly into the brain showed faster and more effective tumor suppression in mouse models compared to traditional intravenous delivery, suggesting that localized treatment may reduce systemic side effects and improve outcomes for children with ATRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Theruvath, J., Sotillo, E., Mount, CW., et al.[2022]

B7-H3 CAR T cells have shown significant antitumor activity in various pediatric solid tumor models, including osteosarcoma and medulloblastoma, indicating their potential as a treatment option for relapsed pediatric malignancies.

The effectiveness of B7-H3 CAR T cells is linked to the density of the B7-H3 antigen on tumor cells, suggesting that this therapy could be selectively effective against tumors with high antigen expression while minimizing effects on normal tissues with lower expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Majzner, RG., Theruvath, JL., Nellan, A., et al.[2021]

Malignant central nervous system tumors are the leading cause of cancer death in children, and while treatments like surgery and chemotherapy can be effective, they often lead to significant neurological and cognitive side effects.

Adoptive cell therapy using CAR T cells shows promise for treating pediatric brain tumors, but challenges such as tumor heterogeneity and the blood-brain barrier limit its effectiveness; recent preclinical studies are exploring ways to enhance the safety and efficacy of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy's Potential for Pediatric Brain Tumors. Thomas, P., Galopin, N., Bonérandi, E., et al.[2021]

Intracranial delivery of HER2-targeting CAR-T cells was found to be well tolerated in a small group of 3 patients with central nervous system (CNS) tumors, indicating a potential safe application for this therapy.

This study suggests that targeting HER2 with CAR-T cells could be a promising approach for treating CNS tumors, although further research with larger patient groups is needed to confirm efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors. [2022]

CAR-T cell therapy, while currently approved only for B cell malignancies, shows promising potential for treating pediatric brain tumors, with early clinical trials indicating some positive responses.

Recent preclinical studies have identified new tumor antigens and combination strategies that enhance the effectiveness of CAR-T cells, particularly when administered directly to the tumor site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. Leruste, A., Beccaria, K., Doz, F.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05768880

NCT05768880 | Study of B7-H3, EGFR806, HER2, And ... This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with SC-CAR4BRAIN, an autologous CD4+ and CD8+ T cells lentivirally ...

2. fredhutch.org fredhutch.org/en/research/clinical-trials/trial-details.fh_trial_id_14755.study-of-b7-h3-egfr806-her2-and-il13-zetakine-quad-car-t-cell-locoregional-immunotherapy-for-pediatric-diffuse-intrinsic-pontine-glioma-diffuse.html

Study of B7-H3, EGFR806, HER2, And IL13-Zetakine ... The T cells will then be bioengineered into a second-generation CAR T cell that target B7H3, EGFR806, HER2, and IL13-zetakine on tumor cells.

3. seattlechildrens.org seattlechildrens.org/research/research-studies-clinical-trials/current-studies/brainchild04/

Cancer – BrainChild-04: Phase 1 Study Of B7-H3, ... In this trial, a patient's own T cells are reprogrammed to recognize and target the proteins B7-H3, EGFR806, HER2, AND IL13-zetakine which are present on the ...

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/812783

autologous B7-H3/EGFR806/HER2/IL13-zetakine CAR ... Upon administration, autologous B7-H3/EGFR806/HER2/IL13-zetakine CAR-expressing CD4+/CD8+ T cells SC-CAR4BRAIN target and bind to tumor cells that express B7-H3 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04185038

NCT04185038 | Study of B7-H3-Specific CAR T Cell ... This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39775044/

Intracerebroventricular B7-H3-targeting CAR T cells for ... Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on ...