CAR T-Cell Therapy for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Chemotherapy, Endocrine therapy, Radiation

Disqualifiers: Dialysis, Uncontrolled seizures, Active infection, others

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

Compensation: Varies

Number of Visits: 34

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies the side effects of a new treatment using specially engineered immune cells, called IL13Ralpha2-CAR T cells (a type of CAR T-cell therapy), to target and destroy brain tumor cells. It focuses on conditions like glioblastoma and related diseases affecting the brain's protective membranes. The treatment is administered in cycles and aims to enhance the immune system's ability to fight these tumors. Ideal participants have confirmed leptomeningeal metastases, indicating the cancer has spread to the brain's membranes, and should manage any existing medical devices, like shunts, during the trial. 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 new therapy.

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.

Is there any evidence suggesting that IL13Ralpha2-CAR T cells are likely to be safe for humans?

Research has shown that a new treatment using IL13Ralpha2-CAR T cells is safe for some brain tumor patients. In some studies, patients tolerated this therapy well. Specifically, one study found that delivering these CAR T cells directly to the tumor was safe and showed promising results for some patients. This suggests the treatment might work without causing serious side effects for some individuals. However, as this is an early trial phase, researchers continue to closely monitor patient responses. While information on long-term safety remains limited, early results are encouraging. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for glioblastoma, which often include surgery, radiation, and chemotherapy, IL13Ralpha2-CAR T cells represent a groundbreaking approach by harnessing the power of the immune system. These CAR T cells are engineered to specifically target the IL13Ralpha2 protein, which is often overexpressed in glioblastoma cells, allowing for precise attack on the cancer cells while sparing healthy tissue. This targeted action is what makes researchers optimistic, as it has the potential to improve effectiveness and reduce side effects compared to conventional therapies.

What evidence suggests that IL13Ralpha2-CAR T cells might be an effective treatment for leptomeningeal disease from glioblastoma?

Research has shown that IL13Ralpha2-CAR T cells, which participants in this trial will receive, might help fight brain tumors. These cells are specially designed to attack tumor cells with the IL13Ralpha2 protein, often found in glioblastoma. Early results suggest this therapy could be promising for treating this aggressive cancer, although outcomes have varied. Some studies found that CAR T cells can be safely administered to patients, with mixed results in tumor reduction. Overall, IL13Ralpha2-CAR T cells are being studied as a potential way to improve treatment for glioblastoma. ^{2 3 4 6 7}

Who Is on the Research Team?

Lisa A. Feldman

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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.

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

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)

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• IL13Ralpha2-CAR T Cells

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.

How Is the Trial Designed?

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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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 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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38480922/

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 ... Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04003649

Study Details | NCT04003649 | IL13Ra2-CAR T Cells With ... It is not yet known whether giving IL13Ralpha2-CAR T cells and nivolumab together may work better in treating patients with glioblastoma. Detailed Description.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625001789

Review CAR T cell therapy for glioblastoma CAR T cells have been safely administered through both peripheral and locoregional routes but with variable clinical and radiographic efficacy.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5763077/

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor ... T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM).

5. academic.oup.com academic.oup.com/noa/article/5/1/vdac185/6956903

Tandem chimeric antigen receptor (CAR) T cells targeting ... Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.

6. 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.

7. aacrjournals.org aacrjournals.org/clincancerres/article/21/18/4062/117790/Bioactivity-and-Safety-of-IL13R-2-Redirected

Bioactivity and Safety of IL13Rα2-Redirected Chimeric ... Purpose: A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)–engineered, autologous primary human CD8+ cytotoxic ...