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

Trial Summary

What is the purpose of this trial?

This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain tumors that have come back after a period of improvement (recurrent) or do not respond to treatment (refractory). Cellular immunotherapy (IL13(EQ)BBzeta/CD19t+ T cells) are brain-tumor specific cells that may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Many patients with brain tumor respond to treatment, but then the tumor starts to grow again. Giving chemotherapy in combination with cellular immunotherapy may kill more tumor cells and improve the outcome of treatment.

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.

What data supports the effectiveness of this treatment for pediatric brain cancer?

Research shows that IL13Rα2-targeted CAR T cells have demonstrated promising anti-tumor activity in glioblastoma (a type of brain cancer) models, with improved survival in mice and some clinical benefits in pediatric patients. Additionally, CD19 CAR T cells have shown high remission rates in leukemia, suggesting potential for similar therapies in other cancers. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for pediatric brain cancer?

CAR T-cell therapy has shown potential in treating certain cancers, but it can cause side effects like cytokine release syndrome (CRS) and neurotoxicity, which can be serious but are often manageable with medical care. Safety data from other conditions suggest that while there are risks, they can be mitigated with careful monitoring and treatment. ^{1 3 6 7 8}

How is CAR T-Cell Therapy for Pediatric Brain Cancer different from other treatments?

This treatment is unique because it uses specially engineered T-cells to target a specific protein (IL13Rα2) found on brain cancer cells, which is not present in normal brain tissue, potentially reducing side effects. Additionally, the therapy is delivered directly into the brain's ventricles, which may enhance its effectiveness compared to traditional systemic treatments. ^{1 2 4 5 7}

Research Team

Leo D Wang

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells. [2023]

3. England 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). [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma. [2022]

5. United States 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. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. [2021]