CAR T-Cell Therapy for Glioblastoma

Overseen by Lisa A. Feldman

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: City of Hope Medical Center

Must not be taking: Chemotherapy, Endocrine therapy, Radiation

Disqualifiers: Dialysis, Uncontrolled seizures, Active infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This phase I trial investigates the side effects of brain tumor-specific immune cells (IL13Ralpha2-CAR T cells) in treating patients with leptomeningeal disease from glioblastoma, ependymoma, or medulloblastoma. Immune cells are part of the immune system and help the body fight infections and other diseases. Immune cells can be engineered to destroy brain tumor cells in the laboratory. IL13Ralpha2-CAR T cells is brain tumor specific and can enter and express its genes in immune cells. Giving IL13Ralpha2-CAR T cells may better recognize and destroy brain tumor cells in patients with leptomeningeal disease from glioblastoma, ependymoma or medulloblastoma.

Do I need to stop my current medications for the trial?

Yes, you will need to stop taking chemotherapy, endocrine therapy, and radiation one week before and during the first 4 cycles of the study.

What data supports the effectiveness of the treatment IL13Ralpha2-CAR T cells for glioblastoma?

Research shows that IL13Ralpha2-CAR T cells can specifically target and kill glioblastoma cells that have a certain marker (IL13Ralpha2) without affecting normal brain cells. In a study, a patient with glioblastoma experienced tumor shrinkage after receiving this treatment, and the positive effects lasted for several months. ^{1 2 3 4 5}

Is CAR T-Cell Therapy targeting IL13Rα2 safe for humans?

In a clinical trial, CAR T-Cell Therapy targeting IL13Rα2 was given to a patient with glioblastoma, and no severe toxic effects were observed. This suggests that the treatment may be generally safe in humans. ^{1 3 4 5 6}

What makes IL13Ralpha2-CAR T-cell therapy unique for treating glioblastoma?

IL13Ralpha2-CAR T-cell therapy is unique because it specifically targets the IL13Rα2 protein, which is highly expressed in glioblastoma but not in normal brain tissue, reducing the risk of harming healthy cells. This therapy involves genetically modifying T cells to recognize and attack glioblastoma cells, offering a promising approach for patients with this aggressive cancer. ^{2 3 4 5 6}

Research Team

Lisa A. Feldman

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with leptomeningeal disease from glioblastoma, ependymoma, or medulloblastoma. They must have a life expectancy of at least 8 weeks, be able to tolerate certain medical procedures and medications, not require dialysis or supplemental oxygen, and agree to use birth control. Those with other active cancers or infections like hepatitis B/C or HIV can't join.

Inclusion Criteria

I can care for myself but may need occasional help.

I am not pregnant or will use birth control during and after the study.

My shunt valve is programmable and can be turned off for 48 hours.

Exclusion Criteria

I am willing to pause my current cancer treatments for the study.

Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

You have a condition where your immune system attacks your own body.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Follow-up at 30 days, months 3, 6, 9, 12, and then yearly

Treatment Details

Interventions

• IL13Ralpha2-CAR T Cells (CAR T-cell Therapy)

Trial Overview The trial tests IL13Ralpha2-CAR T cells designed to target brain tumor-specific immune cells in patients with specific types of brain tumors that have spread. It's a phase I study focusing on the safety and how well these engineered immune cells work against the cancer.

Participant Groups

Group I: Treatment (IL13Ralpha2-CAR T cells) Experimental Treatment 1 Intervention

Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Robert Stone

City of Hope Medical Center

Chief Executive Officer since 2014

Juris Doctorate from the University of Chicago, Bachelor's degree in Political Science from the University of Redlands

Sumanta (Monty) Pal

City of Hope Medical Center

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

The study demonstrates a novel immunotherapy approach targeting malignant glioma by using cytotoxic T lymphocytes (CTL) that are specifically induced to recognize the IL-13 receptor alpha2 (IL-13Ralpha2) epitope, which is unique to glioma cells.

Induced CTLs showed effective lysis of glioma cells expressing the IL-13Ralpha2(345-353) peptide, indicating potential for targeted treatment in HLA-A2 patients, while their activity was inhibited by anti-HLA class I antibodies, highlighting the mechanism of action involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of cytotoxic T lymphocytes specific to malignant glioma using T2 cells pulsed with HLA-A2-restricted interleukin-13 receptor alpha 2 peptide in vitro. Jiang, X., Lu, X., Liu, R., et al.[2019]

A specific CTL epitope derived from the IL-13 receptor alpha2-chain (IL-13Ralpha2) was identified, which is overexpressed in glioblastoma multiforme, and can stimulate CD8+ T cells to produce IFN-gamma and kill glioma cells.

The IL-13Ralpha(345-354) peptide demonstrated effective lytic activity against glioma cell lines, suggesting its potential use in peptide-based vaccines for glioma treatment and as a marker for T-cell immune responses in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain. Okano, F., Storkus, WJ., Chambers, WH., 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 YYB-103 CAR T cells demonstrated selective targeting and toxicity against malignant glioma cells expressing IL13Rα2, while sparing cells that express IL13Rα1, indicating a promising therapeutic approach for treating glioblastoma.

Both intravenous and intracerebroventricular administration of YYB-103 CAR T cells significantly reduced tumor volume and improved survival in mouse models, suggesting effective delivery across the blood-brain barrier and potential for clinical application in patients with recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study. Kim, K., Gwak, HS., Han, N., et al.[2021]

A patient with recurrent multifocal glioblastoma treated with IL13Rα2-targeted CAR T cells showed no severe toxic effects (grade 3 or higher) after multiple infusions over 220 days, indicating a favorable safety profile for this therapy.

The treatment resulted in significant tumor regression in both intracranial and spinal tumors, with a sustained clinical response lasting 7.5 months, alongside increased cytokine and immune cell levels in the cerebrospinal fluid, suggesting effective immune activation against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. Brown, CE., Alizadeh, D., Starr, R., et al.[2023]

The study developed four CAR T cells using IL13 muteins and found that these cells effectively recognized and killed glioblastoma cells expressing IL13Rα1 and IL13Rα2, demonstrating their potential for targeted immunotherapy.

Among the CAR T cells tested, only those with the E13K amino acid substitution showed significant anti-tumor activity in vivo, leading to improved survival in treated animals, highlighting the importance of specific modifications in CAR design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. Krebs, S., Chow, KK., Yi, Z., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

Induction of cytotoxic T lymphocytes specific to malignant glioma using T2 cells pulsed with HLA-A2-restricted interleukin-13 receptor alpha 2 peptide in vitro. [2019]

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

Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain. [2021]

3. 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]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study. [2021]

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

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. [2023]

6. England pubmed.ncbi.nlm.nih.gov

T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. [2021]