CAR T-Cell Therapy for Brain Tumor

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Bevacizumab, Immunosuppressants, others

Disqualifiers: Uncontrolled seizures, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 36

Duration: 4 weeks

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial tests the safety, side effects and best dose of TGFβR2KO/IL13Rα2 chimeric antigen receptor (CAR) T-cells given within the skull (intracranial) in treating patients with glioblastoma or IDH-mutant grade 3 or 4 astrocytoma that has come back after a period of improvement (recurrent) or that is growing, spreading, or getting worse (progressive). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. When the cells are taken from the patient's own blood, it is known as autologous. Then the gene for special receptors that bind to a certain proteins on the patient's tumor cells are added to the T cells in the laboratory. The special receptors are called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain tumors. Giving TGFβR2KO/IL13Rα2 CAR T cells may be safe, tolerable, and/or effective in treating patients with recurrent or progressive glioblastoma or grade 3 or 4 IDH-mutant astrocytoma.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on active bevacizumab therapy, you cannot participate in the trial.

Is CAR T-Cell Therapy for Brain Tumors safe?

CAR T-Cell Therapy targeting IL13Rα2 for brain tumors has shown to be generally safe in humans, with no severe toxic effects reported in some studies. In one study, no dose-limiting toxicities were observed, and only mild side effects like headache and liver enzyme elevation were noted. ^{1 2 3 4 5}

What makes the TGFβR2KO/IL13Rα2 CAR T-Cell treatment unique for brain tumors?

This treatment is unique because it uses CAR T-cells specifically engineered to target IL13Rα2, a protein found on glioblastoma cells but not on normal brain cells, allowing for precise targeting of tumor cells while sparing healthy tissue. Additionally, the TGFβR2KO component helps the T-cells resist the immunosuppressive environment of the tumor, potentially improving their effectiveness. ^{1 6 7 8 9}

What data supports the effectiveness of this treatment for brain tumors?

Research shows that IL13Rα2-specific CAR T-cells can effectively target and kill glioma cells, which are a type of brain tumor cell, without affecting normal brain cells. Additionally, modifying CAR T-cells to resist TGFβ, a substance that helps tumors evade the immune system, has been shown to improve their ability to fight brain tumors in animal studies. ^{1 4 9 10 11}

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 patients with recurrent or progressive glioblastoma or grade 3/4 IDH-mutant astrocytoma. Participants must have a tumor that has returned after treatment or is worsening. Specific eligibility criteria are not provided, but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval

My cancer has returned and grown after treatment and it's been 3 months since my last radiation therapy.

Alanine aminotransferase (ALT) ≤ 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)

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 still experiencing side effects from my previous cancer treatment.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit (in-person)

Leukapheresis and Surgical Resection

Patients undergo leukapheresis and standard of care surgical resection with or without placement of Rickham catheter

1 week

1 visit (in-person)

Treatment

Patients receive autologous TGFβR2KO/IL13Rα2-CAR T cells intracranially once weekly for up to 4 cycles (28 days)

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Visits on day 30, months 3, 6, 9, and 12

Long-term Follow-up

Participants are followed yearly for up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• TGFβR2KO/IL13Rα2 CAR T-Cells

Trial Overview The trial tests TGFβR2KO/IL13Rα2 CAR T-cell therapy given intracranially to see if it's safe and effective against certain brain tumors. It involves modifying the patient's own immune cells to attack tumor cells and monitoring the results using various imaging techniques.

How Is the Trial Designed?

Group I: Treatment (TGFβR2KO/IL13Rα2 CAR T-cells) Experimental Treatment 9 Interventions

Patients undergo leukapheresis and standard of care surgical resection with or without placement of Rickham catheter. Starting on day 0, patients receive autologous TGFβR2KO/IL13Rα2-CAR T cells intracranially over approximately 5 minutes QW. Cycles repeat weekly for up to 4 cycles (28 days) in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles if they continue to meet infusion criteria and have doses available for infusion. Patients also undergo CSF and blood sample collection and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) and MRI throughout the study. Additionally, patients may undergo echocardiography at screening.

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]

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]

In a phase I clinical trial involving six pediatric brain tumor patients, IL13BBζ-CAR T cell therapy showed promise, with three out of five evaluable patients experiencing transient benefits, although these did not meet the strict criteria for response.

The therapy was well-tolerated, with no dose-limiting toxicities reported, and serious adverse events were minimal, suggesting a favorable safety profile for this innovative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis. Wang, L., Oill, AT., Blanchard, M., et al.[2023]

Infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells in eight patients with GD2-positive glioblastoma (GBM) was found to be safe and well tolerated, with no severe adverse events reported.

Of the eight patients, four experienced a partial response lasting between 3 to 24 months, indicating that 4SCAR-T cells can exert anti-GBM activity, with a median overall survival of 10 months post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Liu, Z., Zhou, J., Yang, X., et al.[2023]

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]

A new preclinical mouse model using D-270 MG xenografts effectively mimics the invasive growth patterns of human glioblastoma (GBM), allowing for better study of potential treatments.

T cells engineered with chimeric antigen receptors targeting the EGFRvIII mutation in GBM were able to migrate to invasive tumor areas, suppress tumor growth, and improve survival in mice, indicating a promising approach for immunotherapy in treating GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. Miao, H., Choi, BD., Suryadevara, CM., et al.[2023]

Citations

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

Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Regulatory T cells promote glioma cell stemness through TGF-β-NF-κB-IL6-STAT3 signaling. [2022]

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

Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models. [2020]

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

Expression of a restrictive receptor for interleukin 13 is associated with glial transformation. [2019]

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

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

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

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]

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

Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. [2023]

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

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

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

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. [2023]