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

Trial Summary

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.

What data supports the idea that CAR T-Cell Therapy + Immunotherapy for Glioblastoma is an effective treatment?

The available research shows that CAR T-Cell Therapy targeting IL13Rα2 is promising for treating glioblastoma. In one study, mice treated with IL13Rα2-specific CAR T cells showed significant survival advantages compared to those that did not receive the treatment. Another study demonstrated that these CAR T cells, when modified with IL15, had greater antiglioma activity and persisted longer, leading to better outcomes. Additionally, a case report highlighted that direct delivery of CAR T cells into the cerebrospinal fluid completely eliminated a patient's brain and spinal tumors for 7.5 months, allowing the patient to resume normal activities. These findings suggest that this treatment can be more effective than traditional therapies like surgery, radiation, and chemotherapy, which often result in frequent recurrences. ^{1 2 3 4 5}

What safety data exists for CAR T-Cell Therapy and Immunotherapy for Glioblastoma?

The safety data for CAR T-Cell Therapy targeting IL13Rα2 in glioblastoma includes several findings: IL13Rα2-specific CAR T cells have shown no cross-reactivity to IL13Rα1, which is important for minimizing off-target effects. Second-generation CARs with 4-1BB costimulation have demonstrated superior selectivity and antitumor potency, reducing off-target reactivity. CD4+ CAR T cells have shown superior long-term antitumor activity compared to CD8+ CAR T cells, indicating a potential safety advantage in maintaining effector function. Additionally, tandem CAR T cells targeting both HER2 and IL13Rα2 have shown enhanced antitumor efficacy and reduced antigen escape, suggesting improved safety and effectiveness. Overall, these studies indicate promising safety profiles for IL13Rα2-targeted CAR T-cell therapies in glioblastoma treatment. ^{1 2 4 6 7}

Is the treatment IL13Ralpha2 CAR T cells a promising treatment for glioblastoma?

Yes, IL13Ralpha2 CAR T cells are a promising treatment for glioblastoma. They specifically target cancer cells without affecting normal brain cells, show strong anti-tumor activity, and can improve survival. They also help activate the body's own immune system to fight the tumor, making them a powerful option for treating this type of brain cancer. ^{1 2 3 6 8}

What is the purpose of this trial?

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 patients with glioblastoma that has come back (recurrent) or does not respond to treatment (refractory). Biological therapies, such as IL13Ralpha2-CAR T cells, use substances made from living organisms that may attack specific glioma cells and stop them from growing or kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving IL13Ralpha2-CAR T cells and nivolumab together may work better in treating patients with glioblastoma.

Research Team

Behnam Badie

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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]

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]

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

Targeting Glioblastoma with CAR T Cells. [2019]

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

Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. [2021]

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

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. [2018]

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

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. [2019]

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

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. [2022]

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

IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. [2022]