CAR T-Cell Therapy + Immunotherapy for Glioblastoma

Overseen By Behnam Badie, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Steroids, CTLA-4 inhibitors

Disqualifiers: Autoimmune disease, Uncontrolled seizures, Active infection, 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: 35

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating glioblastoma, a challenging brain cancer that either recurs or resists standard treatments. Researchers are investigating whether a combination of CAR T-cell therapy (which uses modified immune cells) and immunotherapy drugs can more effectively target cancer cells. Participants will receive various combinations of these treatments to determine the most effective one. This trial may suit individuals with glioblastoma that has returned or is unresponsive to treatment, particularly if their tumors have a specific marker. 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 have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are steroid-dependent, requiring more than 6 mg of dexamethasone per day. It's best to discuss your current medications with the study team.

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

Research shows that a special type of immune cell, called IL13Ralpha2-CAR T cells, targets and destroys brain tumor cells. Trials have tested these cells for treating glioblastoma, a type of brain cancer. Previous studies have demonstrated that these CAR T cells can be used alone or with other drugs like nivolumab and ipilimumab.

Nivolumab and ipilimumab help the immune system attack cancer cells and have been used safely in other cancer treatments, though they can cause side effects like tiredness and skin rash.

Since this trial is in its early stages, it focuses primarily on safety. Researchers closely monitor how well people tolerate the treatment. Early trials like this one often start with small doses to check for any serious side effects.

In summary, while IL13Ralpha2-CAR T cells and their combination with nivolumab and ipilimumab are still under study, early research suggests these treatments could be safe. However, as this is an early trial, monitoring participant responses to the treatment remains crucial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine CAR T-cell therapy with immunotherapy, offering a new approach to tackling glioblastoma. Unlike standard treatments like surgery, radiation, and chemotherapy, these investigational therapies use genetically engineered T-cells to specifically target and attack cancer cells. The IL13Ralpha2 CAR T cells are designed to hone in on a particular cancer marker, potentially leading to more precise and effective treatment. Additionally, by incorporating drugs like nivolumab and ipilimumab, which help boost the immune system's response, these treatments aim to enhance the body's natural ability to fight the tumor. This approach could lead to improved outcomes for patients who have limited options with existing therapies.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research has shown that a special type of immune cell, called IL13Ralpha2-CAR T cells, can locate and destroy glioblastoma cells by recognizing a unique protein on them. This approach has shown promise in early studies for treating brain tumors. In this trial, participants in different arms will receive various combinations of treatments. One arm will receive IL13Ralpha2-CAR T cells alone. Another arm will receive these CAR T cells with nivolumab, a drug that aids the immune system, which studies suggest can enhance this treatment's effectiveness. Additionally, a third arm will combine nivolumab with another immune-boosting drug, ipilimumab, alongside CAR T cells, potentially further strengthening the body's ability to fight the cancer. Early findings suggest these combinations could help slow the growth and spread of glioblastoma. ^{1 3 4 6 7}

Who Is on the Research Team?

Behnam Badie

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with grade IV glioblastoma (GBM) or those whose lower-grade glioma has progressed to GBM after standard treatment. Participants must have a life expectancy of at least 4 weeks, be able to use birth control, and not require high doses of steroids. They can't join if they've had certain heart issues without clearance, uncontrolled seizures, active infections needing antibiotics, or are pregnant/breastfeeding.

Inclusion Criteria

Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be

Documented informed consent of the participant and/or legally authorized representative. Assent, when appropriate, will be obtained per institutional guidelines.

My cancer has returned or worsened after treatment, and it's been over 12 weeks since my last radiation therapy.

Exclusion Criteria

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).

I am not pregnant or breastfeeding.

I am still experiencing side effects from my previous cancer treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Therapy

Patients receive nivolumab and ipilimumab as neoadjuvant therapy to assess safety and feasibility

2 weeks

1 visit (in-person)

Adjuvant Therapy

Patients receive IL13Ralpha2 CAR T cells and nivolumab, with treatment repeating weekly for up to 4 cycles

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Visits at 30 days, 3, 6, and 12 months, then annually

What Are the Treatments Tested in This Trial?

Interventions

• IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
• Ipilimumab
• Nivolumab

Trial Overview The study is testing IL13Ralpha2-CAR T cells alone or combined with nivolumab and ipilimumab in patients with recurrent or refractory GBM. It aims to see how well these treatments work together compared to when the CAR T cells are used by themselves.

How Is the Trial Designed?

Group I: Arm III (IL13Ra2 CAR T cells) Experimental Treatment 3 Interventions

Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly at the discretion of the principal investigator and oncologist.

Group II: Arm II (nivolumab, IL13Ra2 CAR T cells) Experimental Treatment 4 Interventions

Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

Group III: Arm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) Experimental Treatment 5 Interventions

Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/intracranital ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells is already approved in United States for the following indications:

Approved in United States as IL13Ralpha2 CAR T cells for:

• Stage IIIC or IV melanoma
• Metastatic solid tumors

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

A case report demonstrated that CAR T cells targeting IL13Rα2 were effective in treating recurrent multifocal leptomeningeal glioblastoma, leading to complete tumor elimination.

The therapy, delivered directly into the cerebrospinal fluid, was well tolerated by the patient, allowing them to resume normal activities for 7.5 months after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Glioblastoma with CAR T Cells. [2019]

The development of a bispecific CAR T cell (TanCAR) targeting both HER2 and IL13Rα2 in glioblastoma showed enhanced antitumor activity and improved survival in a murine model, suggesting a promising approach to overcome antigen escape.

TanCAR T cells demonstrated sustained activation and the ability to engage both antigens simultaneously, leading to improved T cell functionality compared to traditional single-target CAR T cells, which may help in controlling glioblastoma more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. Hegde, M., Mukherjee, M., Grada, Z., et al.[2022]

CAR T-cell therapy not only targets tumors directly but also activates the body's own immune system, enhancing the response against glioblastoma (GBM) by promoting T-cell memory and activating myeloid cells.

The effectiveness of CAR T-cell therapy in GBM is significantly linked to IFNγ signaling, which helps remodel the tumor microenvironment to support stronger antitumor immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. Alizadeh, D., Wong, RA., Gholamin, S., et al.[2022]

Transgenic expression of IL15 in CAR T cells targeting the IL13Rα2 antigen significantly enhances their ability to proliferate, survive, and produce cytokines, leading to improved antiglioma activity in a glioblastoma model.

Despite the improved persistence and effectiveness of IL13Rα2-CAR.IL15 T cells, gliomas that recurred after treatment showed reduced IL13Rα2 expression, indicating the need for strategies that target multiple tumor antigens to prevent antigen loss and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. Krenciute, G., Prinzing, BL., Yi, Z., et al.[2018]

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]

CD4+ CAR T cells targeting the IL-13 receptor α2 showed superior long-term antitumor effects against glioblastoma compared to CD8+ CAR T cells, which became exhausted quickly after initial activation.

The study suggests that maintaining a higher proportion of CD4+ CAR T cells in therapy could enhance the effectiveness of CAR T cell treatments for solid tumors like glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. Wang, D., Aguilar, B., Starr, R., et al.[2019]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04003649

Study Details | NCT04003649 | IL13Ra2-CAR T Cells With ... This phase I trial studies the side effects and how well IL13Ralpha2-CAR T cells work when given alone or together with nivolumab and ipilimumab in treating ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8185049/

CAR T Cell-Based Immunotherapy for the Treatment of ... Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical ...

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

NCT04661384 | Brain Tumor-Specific Immune Cells ... Giving IL13Ralpha2-CAR T cells may better recognize and destroy brain tumor cells in patients with leptomeningeal disease from glioblastoma, ependymoma or ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10035515/

Inclusion of 4-1BB Costimulation Enhances Selectivity and ... Inclusion of 4-1BB costimulation enhances selectivity and functionality of IL13Rα2-targeted chimeric antigen receptor T cells.

5. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/C117233

Clinical Trials Using IL13Ralpha2-specific Hinge-optimized ... NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying il13ralpha2-specific hinge-optimized ...

6. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/C141460

Clinical Trials Using IL13Ralpha2-specific Hinge-optimized ... Review the clinical trials studying il13ralpha2-specific hinge-optimized 4-1bb-co-stimulatory car/truncated cd19-expressing autologous tn/mem cells on this ...

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02208362/

Clinical Trial: NCT02208362 - Malignant Glioma This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma.