CAR T-Cell Therapy for Pediatric Brain Cancer

Recruiting at 2 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Dexamethasone

Disqualifiers: Oxygen dependency, Cardiac arrhythmias, Dialysis, others

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

Compensation: Varies

Number of Visits: 38

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore the safety and effects of combining chemotherapy with a specific type of cellular immunotherapy for treating children with brain tumors that are difficult to treat or have recurred. The treatment uses chemotherapy drugs to halt tumor growth and special immune cells (IL13Ralpha2-specific CAR T cells, a type of cellular immunotherapy) to target and destroy brain tumor cells. Children diagnosed with brain cancer that hasn't responded to standard treatments and have specific tumor markers might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific 'washout' periods (time without taking certain medications) required for some treatments before starting the study. It's best to discuss your current medications with the study team to understand any necessary adjustments.

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

Research has shown that a new treatment, IL13Ralpha2-specific CAR T-cell therapy, may help treat brain tumors. Early results suggest this treatment is generally safe for some patients. One study found that administering these CAR T cells directly to the brain was well-tolerated, and some patients experienced positive outcomes.

The chemotherapy drugs used in this trial, cyclophosphamide and fludarabine, are well-known and have long been used in cancer treatments. They can cause side effects like nausea and low blood cell counts, but doctors can manage these issues effectively.

As this trial is in its early phase, the main goal is to assess safety. This means there might be unknown risks, and the team will closely monitor participants for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for pediatric brain cancer, which often include surgery, radiation, and chemotherapy, this CAR T-cell therapy offers a unique approach. This therapy uses genetically engineered T-cells that are tailored to recognize and attack cancer cells expressing the IL13Ralpha2 marker, a feature not targeted by conventional treatments. Researchers are excited because this treatment harnesses the body's own immune system to fight the cancer more precisely, potentially leading to fewer side effects and better outcomes for young patients. The therapy's innovative delivery directly into the brain may also enhance its effectiveness against these hard-to-reach tumors.

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

Research has shown that a new treatment using IL13Ralpha2-specific CAR T cells could help treat brain tumors. These specially designed immune cells target a protein called IL13Ralpha2, often found in aggressive brain tumors, and can slow tumor growth. Early studies suggest that directly administering these CAR T cells into the brain is safe and may benefit some patients. In this trial, the treatment combines with chemotherapy drugs like cyclophosphamide and fludarabine, potentially enhancing its effectiveness in killing tumor cells and improving outcomes. Although these findings remain in the early stages, they offer hope for treating challenging brain tumors in children. ^{1 2 3 5 6}

Who Is on the Research Team?

Leo D Wang

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for children with IL13Ralpha2 positive brain tumors that have returned or are not responding to treatment. They must have good kidney function, no severe infections, and a certain level of physical ability despite their illness. Children who are pregnant, breastfeeding, or unable to follow the study procedures cannot participate.

Inclusion Criteria

Your ALT and AST levels in the blood are not more than twice the normal limit.

Your liver function test (AST) is not more than twice the upper limit of normal.

Assent, when appropriate, will be obtained per institutional guidelines

Exclusion Criteria

I am on dialysis.

You have tested positive for HIV within the past 4 weeks.

I am not currently being treated for a severe infection or recovering from major surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Patients receive cyclophosphamide and fludarabine intravenously to prepare for CAR T cell therapy

4 days

Daily visits for 4 days

CAR T Cell Treatment

Patients receive autologous IL13(EQ)BBzeta/CD19t+ T cells intraventricularly once a week for up to 4 cycles

4 weeks

Weekly visits for 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Visits at 30 days, 3, 6, 9, and 12 months, then yearly for 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes

Trial Overview The trial tests chemotherapy (cyclophosphamide and fludarabine) combined with cellular immunotherapy using CAR T cells targeting IL13Ralpha2 on tumor cells. It aims to see if this combination can better kill tumor cells in children whose brain cancer has come back or isn't responding.

How Is the Trial Designed?

Group I: Treatment (chemotherapy, IL13(EQ)BBzeta/CD19t+ T cells) Experimental Treatment 3 Interventions

Patients receive cyclophosphamide intravenously IV on days -5 and -4, and fludarabine IV on days -5 to -2. Patients then receive autologous IL13(EQ)BBzeta/CD19t+ T cells intraventricularly over 5 minutes QW on day 0. Treatment with autologous IL13(EQ)BBzeta/CD19t+ T cells repeats every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of IL13(EQ)BBzeta/CD19t+ T cells as long as they continue to meet eligibility criteria and have doses available for infusion.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 case study of a patient with relapsed/refractory B-cell acute lymphoblastic leukemia, lymphodepletion using clofarabine and cyclophosphamide before CAR-T-cell therapy led to successful remission, demonstrating clofarabine's potential as an alternative to fludarabine.

Clofarabine did not impair the effectiveness of the CAR-T cells, as evidenced by the patient's cytokine release syndrome and the absence of minimal residual disease, indicating a successful treatment outcome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. Foti, A., Stein, D., Seidel, D., et al.[2023]

In a study of 133 adults with refractory B-cell malignancies treated with CD19 CAR-T cells, several factors such as acute lymphoblastic leukemia, high levels of CD19+ cells, and preexisting neurologic conditions were linked to an increased risk of neurologic adverse events (AEs).

Patients experiencing severe neurotoxicity showed signs of endothelial activation and increased blood-brain barrier (BBB) permeability, which allowed harmful cytokines to affect the brain, indicating that pre-existing endothelial dysfunction may heighten the risk of neurotoxicity following treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Gust, J., Hay, KA., Hanafi, LA., et al.[2021]

IL13Rα2-specific CAR T cells, designed to target glioblastoma without affecting normal brain tissue, demonstrated effective recognition and destruction of IL13Rα2-positive cancer cells without cross-reactivity to IL13Rα1.

In vivo studies showed that CAR T cells with short spacer regions and specific endodomains significantly improved survival in mice with glioma, indicating their potential as a promising treatment for glioblastoma and similar cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. Krenciute, G., Krebs, S., Torres, D., et al.[2018]

The study developed an optimized CAR T cell therapy targeting the IL-13 receptor α2 (IL13Rα2) for glioblastoma, showing improved anti-tumor activity and T cell persistence compared to earlier CAR T cell designs in mouse models.

Low-dose dexamethasone, commonly used in glioblastoma treatment, does not reduce the effectiveness of CAR T cells, and local delivery of these cells directly into the brain is more effective than intravenous administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma. Brown, CE., Aguilar, B., Starr, R., et al.[2022]

CAR-T cell therapy has shown high remission rates in pediatric patients with CD19+ B-cell malignancies, but challenges remain for treating solid tumors like osteosarcoma due to fewer targets and a hostile tumor environment.

The development of a CAR-T adaptor molecule (EC17 CAM) allows for targeted therapy against folate receptor-positive tumors, enhancing CAR-T cell activation and reducing the risk of severe cytokine release syndrome through careful dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies. Lu, YJ., Chu, H., Wheeler, LW., et al.[2020]

The study demonstrates that second-generation IL13-BBζ CAR T cells show superior proliferation and antitumor potency against glioblastoma compared to first-generation and third-generation CAR designs, indicating enhanced efficacy in targeting the cancer antigen IL13Rα2.

IL13-BBζ CARs also exhibit improved selectivity for the intended tumor target over the unintended target IL13Rα1, which is crucial for minimizing off-tumor effects and enhancing safety in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells. Starr, R., Aguilar, B., Gumber, D., et al.[2023]

Adoptive cellular therapy using CD19 CAR T cells has shown remarkable efficacy in achieving remission in 67-90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), indicating a promising treatment option for this high-risk group.

While CD19 CAR T-cell therapy can lead to significant toxicities such as cytokine release syndrome and neurologic dysfunction, these effects are generally manageable with supportive care, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Tasian, SK., Gardner, RA.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04510051

Study Details | NCT04510051 | CAR T Cells After ... This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain tumors

2. cancer.gov cancer.gov/clinicaltrials/NCI-2020-05158

Chemotherapy and CAR-T Cell Immunotherapy (Brain ... CAR-T cell therapy in combination with chemotherapy may be effective in killing tumor cells and improving the outcome in children with IL13Ralpha2 positive ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04661384

NCT04661384 | Brain Tumor-Specific Immune Cells ... This phase I trial investigates the side effects of brain tumor-specific immune cells (IL13Ralpha2-CAR T cells) in treating patients with leptomeningeal ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38454126/

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in ... These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3990334/

Adoptive transfer of IL13Rα2-specific T cells for the treatment ... Bioinformatic studies demonstrated that expression of IL13Rα2 is associated with increased glioma malignancy grade, mesenchymal signature gene expression, and ...

6. trialx.com trialx.com/clinical-trials/listings/250240/car-t-cells-after-lymphodepletion-for-the-treatment-of-il13r2-positive-recurrent-or-refractory-brain-tumors-in-children/

CAR T Cells After Lymphodepletion for the Treatment of ... This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain ...