A Phase 1 Trial to Evaluate the Safety of IL13Rα2-Targeting Chimeric Antigen Receptor (CAR) T Cells With CRISPR Knockout of TGFβR2 in Patients With Recurrent or Progressive High-Grade Glioma (HGG)

Plain English Summary

Intracranial Genetically Modified Immune Cells (TGFβR2KO/IL13Rα2 CAR T-Cells) for the Treatment of Recurrent or Progressive Glioblastoma or Grade 3 or 4 IDH-Mutant Astrocytoma is a Phase 1 clinical trial sponsored by City of Hope Medical Center studying Recurrent Astrocytoma, IDH-Mutant, Grade 3, Recurrent Astrocytoma, IDH-Mutant, Grade 4, Recurrent Glioblastoma. This trial tests a new type of immune cell therapy (CAR T-cells) designed to target and destroy brain tumor cells. It is for adults with recurrent or progressive high-grade glioma, specifically glioblastoma or IDH-mutant astrocytoma. Participation involves collecting the patient's own immune cells, modifying them in a lab, and then infusing them back into the skull. Alternative treatments may include standard chemotherapy, radiation, or other targeted therapies, depending on the patient's specific condition and prior treatments. The trial aims to enroll 27 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with a confirmed diagnosis of recurrent or progressive high-grade glioma (glioblastoma or IDH-mutant astrocytoma) can join. Patients must have tumors that express a specific protein (IL13Rα2) and have shown progression after previous treatments. Individuals with uncontrolled medical conditions, active infections, or certain other active cancers may not be eligible. Good general health, including adequate blood counts and organ function, is required. This trial is studying Recurrent Astrocytoma, IDH-Mutant, Grade 3, Recurrent Astrocytoma, IDH-Mutant, Grade 4, Recurrent Glioblastoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcomes measure how safe the new therapy is by tracking serious side effects, including a specific immune reaction called cytokine release syndrome, within the first month of treatment. The specific primary outcome measures are: Dose-limiting toxicities (DLTs) (Up to 28 days); Incidence of grade 3+ adverse events (AEs) (Up to 30 days after last dose of study drug); Incidence of cytokine release syndrome (Up to 30 days after last dose of study drug); Incidence of all other AEs (Up to 30 days after last dose of study drug). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial addresses a critical need for new treatments for recurrent or progressive high-grade gliomas, which have limited effective options after initial therapy. This research targets Recurrent Astrocytoma, IDH-Mutant, Grade 3, Recurrent Astrocytoma, IDH-Mutant, Grade 4, Recurrent Glioblastoma, where improved treatment options are needed.

Investor Insight

This Phase 1 trial represents an early-stage investment in a novel CAR T-cell therapy for a challenging brain cancer, with potential for significant future market if proven safe and effective. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of this experimental therapy, and how it compares to other available treatments. Participation will involve blood draws, potential surgery for a catheter, and receiving the modified immune cells directly into the brain. You will need to attend regular follow-up appointments for monitoring of side effects and treatment response. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 27 participants

Interventions

• PROCEDURE: Biospecimen Collection — Undergo CSF and blood sample collection
• BIOLOGICAL: Chimeric Antigen Receptor T-Cell Therapy — Given autologous TGF-betaR2KO/IL13R-alpha2-CAR T cells intracranially
• PROCEDURE: Echocardiography — Undergo echocardiography
• OTHER: Fludeoxyglucose F-18 — Undergo FDG-PET
• PROCEDURE: Intracranial Catheter Placement — Undergo placement of Rickham catheter

Primary Outcomes

• Dose-limiting toxicities (DLTs) (Up to 28 days)
• Incidence of grade 3+ adverse events (AEs) (Up to 30 days after last dose of study drug)
• Incidence of cytokine release syndrome (Up to 30 days after last dose of study drug)
• Incidence of all other AEs (Up to 30 days after last dose of study drug)

Secondary Outcomes

• Overall response rate (At 3, 6, and 9 months)
• Complete response rate (At 3, 6, and 9 months)
• Overall survival (OS) (From cycle 1 to last contact or death from any cause, assessed at 9 months)
• Ability to meet the TGFβR2KO/IL13Rα2-CAR T cell dose requirements (product feasibility) (Up to 1 year)
• Ability to meet product release requirements (product feasibility) (Up to 1 year)

Full Eligibility Criteria

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated main consent is processed. However, the research participant is allowed to proceed with surgery/Rickham placement and CAR T cell infusion only after the translated main consent form is signed
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: ≥ 18 years
* Karnofsky performance status (KPS) ≥ 70%, Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Life expectancy ≥ 4 weeks
* If the participant has a shunt, they must be informed of the following:

  * If the shunt is not programmable, the participant must be willing to have a programmable shunt placed prior to CAR T cell infusion, and
  * If the shunt is programmable, in order to proceed to the treatment portion of the study, the participant must be able to tolerate their shunt being functionally closed for at least 2 hours
* Participant has a prior histologically-confirmed diagnosis of a grade 3 or 4 IDH-mutant astrocytoma or glioblastoma, or has a prior histologically-confirmed diagnosis of a grade 2 or 3 astrocytoma and now has radiographic progression consistent with grade 3 or 4 IDH-mutant astrocytoma
* Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy, and ≥ 12 weeks after completion of front-line radiation therapy
* COH clinical pathology confirms IL13Rα2+ tumor expression by immunohistochemistry (H-score ≥ 80)
* No known contraindications to leukapheresis, steroids, or tocilizumab
* White blood cell (WBC) \> 2000 /dl (or absolute neutrophil count \[ANC\] ≥ 1,000/mm\^3) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Platelets ≥ 75,000/mm\^3 (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Hemoglobin ≥ 8g/dl (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Aspartate aminotransferase (AST) ≤ 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Serum creatinine ≤ 1.6 mg/dL (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Oxygen (O2) saturation ≥ 95% on room air (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Seronegative for HIV antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (to be performed within 14 days prior to leukapheresis unless otherwise stated)

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Owing to higher frequency of wound-related complications, participants who require active bevacizumab therapy at the time of enrollment are excluded
* Participant has not yet recovered from toxicities of prior therapy
* Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Clinically significant uncontrolled illness
* Active autoimmune disease requiring systemic immunosuppressive therapy
* Active infection requiring intravenous (IV) antibiotics (e.g., minor scalp infection is not an exclusion)
* Known history of human immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
* Other active malignancy. Note: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study proced

Trial Locations

• City of Hope Medical Center, Duarte, California, United States

Frequently Asked Questions

Related Conditions

• Glioblastoma
• Astrocytoma
• High-Grade Glioma
• Brain Cancer
• Recurrent Glioma
• Progressive Glioma
• IDH-Mutant Glioma
• Central Nervous System Tumors
• Neuro-oncology
• Immunotherapy

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