CAR T-cell Therapy for Glioblastoma

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Immunosuppressants, Bevacizumab

Disqualifiers: Hepatitis, Cardiovascular, Autoimmune, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new CAR T-cell therapy for glioblastoma, a type of brain cancer that has returned after treatment. The therapy, known as CART-EGFR-IL13Ra2 Cells, uses modified immune cells to target specific markers on cancer cells. Participants will receive different doses to determine the safest and most effective one. This trial may suit those with glioblastoma that has recurred after radiation and who have specific genetic markers in their tumor. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on bevacizumab, you must not have received it within 3 months before eligibility confirmation.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research shows that the treatment under study, called CART-EGFR-IL13Ra2 cells, appears safe in early human tests. In earlier studies, researchers administered these specially designed white blood cells directly into the brain. Participants handled the treatment well, experiencing no serious side effects. Some minor side effects occurred but were manageable.

This is early research, and while initial results are promising, further studies are necessary to confirm the treatment's safety and effectiveness. This trial is part of ongoing research to ensure the treatment is safe and beneficial for patients with glioblastoma, a type of brain cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for glioblastoma?

Most treatments for glioblastoma, like surgery, radiation, and chemotherapy, aim to remove or shrink tumors but often struggle with fully eradicating cancer cells. CART-EGFR-IL13Ra2 is unique because it uses CAR T-cell therapy, a method that re-engineers a patient's own immune cells to specifically target and destroy glioblastoma cells. This treatment is administered via intrathecal administration, directly into the cerebrospinal fluid, ensuring that the modified cells reach the brain more effectively. Researchers are excited about this approach because it offers a targeted attack on cancer cells, potentially leading to better outcomes with fewer side effects compared to traditional treatments.

What evidence suggests that CART-EGFR-IL13Ra2 cells could be an effective treatment for glioblastoma?

Research shows that a new treatment, CART-EGFR-IL13Ra2 cells, a form of CAR T-cell therapy, may help treat recurring glioblastoma, a type of brain cancer. This trial will explore different dosing regimens of CART-EGFR-IL13Ra2 cells, which target specific proteins, EGFR and IL13Rα2, found on glioblastoma cells. Early studies of similar treatments have shown that these CAR T-cells can be safely delivered into the brain and were well-tolerated by patients. Targeting these proteins on tumor cells suggests that the therapy might help the immune system attack and destroy the cancer cells. Although still in early stages, these findings offer hope for those fighting this aggressive brain cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Stephen Bagley, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent glioblastoma, IDH-wildtype, after radiotherapy. Candidates must have adequate organ function, EGFR-amplified tumors confirmed by specific tests, and agree to use birth control. Excluded are those with active hepatitis B/C, severe comorbidities, recent bevacizumab treatment, autoimmune diseases needing high-dose steroids or pregnant/nursing women.

Inclusion Criteria

My glioblastoma has returned after radiation treatment.

My doctor recommends surgery or a biopsy to manage or confirm my cancer's return.

Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria

I am allergic to some ingredients in the study medication.

I have not received bevacizumab in the last 3 months.

I have an active hepatitis B or C infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single fixed dose of CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0, with dose escalation based on cohort assignment

4 weeks

1 visit (in-person) for administration, followed by staggered monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with formal DLT evaluations performed after the 3rd subject in each cohort reaches the Day 28 safety follow-up visit

4 weeks

1 visit (in-person) for safety follow-up

Long-term follow-up

Participants are monitored for progression-free survival and objective response rate over an extended period

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CART-EGFR-IL13Ra2 Cells

Trial Overview The study is testing the safety of CART-EGFR-IL13Ra2 cells in patients whose glioblastoma has returned despite prior treatments. It's an early-phase trial where participants receive genetically modified T cells targeting two specific molecules on their cancer.

How Is the Trial Designed?

Group I: Cohort 4 Experimental Treatment 1 Intervention

Participants will receive two doses of CART-EGFR-IL13Rα2 cells, to determine the optimal dose schedule.

Group II: Cohort 3 Experimental Treatment 1 Intervention

Participants will receive a single fixed dose of 5x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.

Group III: Cohort 2 Experimental Treatment 1 Intervention

Participants will receive a single fixed dose of 2.5x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.

Group IV: Cohort 1 Experimental Treatment 1 Intervention

Participants will receive a single fixed dose of 1x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.

Group V: Cohort -1 Experimental Treatment 1 Intervention

Participants will receive a single fixed dose of 5x10\^6 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.

CART-EGFR-IL13Ra2 Cells is already approved in United States for the following indications:

Approved in United States as CART-EGFR-IL13Ra2 for:

• Glioblastoma

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Tmunity Therapeutics

Industry Sponsor

Trials

7

Recruited

140+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Kite Pharma (a Gilead Company)

Collaborator

Tmunity Therapeutics, a wholly owned subsidiary of Kite Pharma (a Gilead company)

Collaborator

Trials

2

Recruited

70+

Published Research Related to This Trial

The study found that the interleukin 13 receptor (IL13R) is highly over-expressed in glioblastoma multiforme (GBM) tumors compared to normal brain tissues, making it a specific target for therapy.

Compared to other growth factor receptors like the epidermal growth factor receptor (EGFR), IL13R showed more consistent and homogeneous binding in GBM samples, suggesting it could be a promising candidate for delivering anti-GBM treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Debinski, W., Gibo, DM., Slagle, B., et al.[2020]

A novel chimeric antigen receptor (CAR) T cell therapy targeting the IL13 receptor α-2 (IL13Rα2) shows promise in treating glioblastoma multiforme (GBM), demonstrating effective tumor cell killing and increased survival in animal models.

While the IL13 dTc therapy effectively targets GBM cells, it also retains some activity against normal cells expressing IL13Rα1, indicating a potential safety concern for systemic administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. Kong, S., Sengupta, S., Tyler, B., 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]

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]

IL13Rα2 is a promising target for immunotherapy in high-grade gliomas, as it is expressed on both glioma stem-like cancer initiating cells (GSCs) and more differentiated tumor cells, making them both susceptible to treatment.

Genetically engineered IL13Rα2-specific CD8(+) T cells (IL13-zetakine(+) CTLs) effectively recognized and killed IL13Rα2-positive GSCs and differentiated cells in laboratory tests and showed strong antitumor activity in mouse models, suggesting a potential new approach to treat resistant glioma populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells. Brown, CE., Starr, R., Aguilar, B., et al.[2022]

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]

Two humanized CAR T cell constructs targeting IL-13Rα2 showed superior tumor inhibition in a glioma model, with Hu08BBz achieving a 75% reduction in tumor growth compared to existing therapies.

The study also indicates that combining IL-13Rα2 CAR T cells with immune checkpoint blockade enhances their efficacy, suggesting a promising approach for both canine and human glioma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. Yin, Y., Boesteanu, AC., Binder, ZA., et al.[2020]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05168423

Study Details | NCT05168423 | CART-EGFR-IL13Ra2 in ... This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.102

A phase 1 study of intracerebroventricular (ICV) delivery ... Here we report the results from the dose exploration phase of a phase 1 trial investigating ICV-delivered, bivalent CAR T-cells targeting EGFR ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06973096?term=EGFR,%20glioblastoma&viewType=Table&rank=2

CART-EGFR-IL13Ra2 in Newly Diagnosed GBM Following ... This is an open-label phase 1 study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous T cells co-expressing two ...

4. nature.com nature.com/articles/s41698-024-00753-0

CAR-T cell therapy for the treatment of adult high-grade ... Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med (2024) https ...

5. 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.

6. cell.com cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(25)00178-9

A review of the first decade of clinical trials CAR T cells have been safely administered through both peripheral and locoregional routes but with variable clinical and radiographic efficacy.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06973096

Study Details | NCT06973096 | CART-EGFR-IL13Ra2 in ... This is an open-label phase 1 study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous T cells co-expressing two ...