Using genetically modified immune cells to treat recurrent brain tumors

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)

This study is testing a new treatment using modified immune cells to see if it can help people with recurring brain tumors feel better and fight their cancer.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 27 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: City of Hope Medical Center (Academic / other)
• Drugs / interventions: tocilizumab, bevacizumab, CAR T, radiation, chimeric antigen receptor
• Locations: 1 site (Duarte, California)
• Trial ID: NCT06815029 on ClinicalTrials.gov

What this trial studies

This phase I trial evaluates the safety and optimal dosage of TGFβR2KO/IL13Rα2 CAR T-cell therapy administered directly into the skull for patients with recurrent glioblastoma or IDH-mutant grade 3 or 4 astrocytoma. The study involves modifying a patient's own T cells in the laboratory to enhance their ability to target and attack tumor cells. Participants will receive multiple cycles of treatment, and the study will assess both the safety and effectiveness of this innovative approach over time.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with recurrent glioblastoma or IDH-mutant astrocytoma who meet specific health criteria.

Not a fit: Patients with non-recurrent brain tumors or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with aggressive brain tumors that are difficult to treat.

How similar studies have performed: While CAR T-cell therapy has shown promise in other cancers, this specific approach for brain tumors is novel and has not been extensively tested.

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 procedures
* 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)

Where this trial is running

Duarte, California

• City of Hope Medical Center — Duarte, California, United States (Recruiting)

Study contacts

• Principal investigator: Behnam Badie — City of Hope Medical Center

Conditions Recurrent Astrocytoma, IDH-Mutant, Grade 3; Recurrent Astrocytoma, IDH-Mutant, Grade 4; Recurrent Glioblastoma