IL13Rα2 CAR-T Cells Secreting Anti-PD-L1 Antibody for Recurrent Malignant Glioma

Official title

A Multicenter, Open-Label, Non-Randomized, Single-Arm Investigator-Initiated Trial to Evaluate the Safety and Efficacy of IL13Rα2 CAR-T Cells Secreting Anti-PD-L1 Antibody in Patients With Recurrent Malignant Glioma

Overview

This clinical study is designed to evaluate the safety and efficacy of IL13Rα2 CAR-T cells secreting anti-PD-L1 antibody in patients with recurrent malignant glioma. This trial is a multicenter, open-label, non-randomized, single-arm investigator-initiated trial (IIT). Patients who have recurrent malignant glioma will receive IL13Rα2 CAR-T cell therapy and will be monitored for safety, adverse events (AEs), and efficacy outcomes, including overall survival (OS) and progression-free survival (PFS). The study will help assess the potential of this innovative therapy in the treatment of glioma and its ability to control tumor growth by targeting both IL13Rα2 and PD-L1.

Detailed description

The primary aim of this study is to evaluate the safety and efficacy of IL13Rα2 CAR-T cells secreting anti-PD-L1 antibody for the treatment of recurrent malignant glioma. Malignant gliomas are aggressive brain tumors with limited treatment options and poor prognosis. Immunotherapy, including CAR-T cells, has shown promise in various cancers, but its application in glioma treatment remains under investigation.

This study will involve patients with recurrent glioma who have failed prior treatments. Participants will receive a single infusion of IL13Rα2 CAR-T cells, which are engineered to recognize and target tumor cells expressing IL13Rα2. The CAR-T cells will be combined with the secretion of anti-PD-L1 antibodies, aimed at overcoming the immune checkpoint inhibition in the tumor microenvironment.

Safety will be assessed by monitoring adverse events (AEs) and cytokine release syndrome (CRS). The efficacy will be evaluated by measuring tumor response, progression-free survival (PFS), and overall survival (OS) over a follow-up period of several months. The study will also assess changes in the immune microenvironment, including immune cell infiltration and expression of immune checkpoint markers.

The trial will be conducted across multiple centers, including major hospitals in China. It aims to provide valuable data on the potential of this dual-target CAR-T therapy in treating gliomas and to assess its feasibility as a clinical treatment option.

Interventions

• Biological IL13Rα2 CAR-T Cells Secreting Anti-PD-L1 Antibody
  Autologous IL13Rα2-targeted CAR-T cells engineered to secrete anti-PD-L1 antibody will be administered after lymphodepleting pretreatment. The study includes peripheral intravenous infusion alone or peripheral intravenous infusion combined with intraventricular injection. Peripheral dose-escalation levels are 1×10\^6 cells/kg, 3×10\^6 cells/kg, and 1×10\^7 cells/kg. In the combined administration strategy, the intraventricular dose is 20%-30% of the peripheral dose, with adjustment based on pati

Primary outcome measures

• Incidence of Grade 3 or Higher Treatment-Related Adverse Events [Time frame: From first CAR-T cell infusion through Day 28]
• Progression-Free Survival [Time frame: Up to 2 years after first CAR-T cell infusion]

Secondary outcome measures (10)

• Incidence and Maximum Grade of Cytokine Release Syndrome [Time frame: From first CAR-T cell infusion through Day 28]
• Incidence and Maximum Grade of Immune Effector Cell-Associated Neurotoxicity Syndrome [Time frame: From first CAR-T cell infusion through Day 28]
• Overall Survival [Time frame: Up to 2 years after first CAR-T cell infusion]
• Objective Response Rate by MRI/PET-CT [Time frame: Assessed at Day 56, Day 84, and every 3 months thereafter up to 2 years]
• Change in Tumor Volume on Imaging [Time frame: Baseline, Day 7, Day 28, Day 56, Day 84, and every 3 months thereafter up to 2 years]
• Change in Quality of Life Score Measured by EORTC QLQ-C30 [Time frame: Baseline, Day 28, Day 56, Day 84, and every 3 months thereafter up to 2 years]
• Change in Karnofsky Performance Status Score [Time frame: Baseline, Day 28, Day 56, Day 84, and every 3 months thereafter up to 2 years]
• Change in Modified Rankin Scale Score [Time frame: Baseline, Day 28, Day 56, Day 84, and every 3 months thereafter up to 2 years]
• Persistence of CAR-T Cells in Peripheral Blood [Time frame: Baseline and multiple post-infusion time points through 2 years]
• Persistence of CAR-T Cells in Cerebrospinal Fluid [Time frame: Post-infusion time points through 2 years]

Eligibility criteria

Inclusion criteria

• Recurrent malignant glioma (WHO grade IV)
• Pathologically confirmed and imaging-defined recurrent glioma
• ECOG score of 0-2
• Age >=18 years
• Male or female
• Life expectancy >3 months

Exclusion criteria

• Severe immune suppression or autoimmune diseases
• Severe cardiac, liver, kidney, or other major organ dysfunction
• Pregnant or breastfeeding women
• Prior treatment with immune checkpoint inhibitors or other immunotherapies
• Other conditions posing significant risk to the patient or preventing adherence to the study protocol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chine — Beijing

Publications

• Li X, Shang X, Liu J, Zhang Y, Jia X, Li H, Wang Y, Gao J, Ma X, Zhang X, Rong X, Gan W, Zhang Y, Chen J, Wang L, Bao Z, He L, Yan X, Liu Y, Shao J, Xiao Z, Wang Z, Zhu H, Wang Z, Wu Y, Huang Y. Intrathecal CRISPR-edited allogeneic IL-13Ralpha2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial. Nat Commun. 2026 Jan 6;17(1):1362. doi: 10.1038/s41467-025-681 PMID 41495049
• Law I, Albert NL, Arbizu J, Boellaard R, Drzezga A, Galldiks N, la Fougere C, Langen KJ, Lopci E, Lowe V, McConathy J, Quick HH, Sattler B, Schuster DM, Tonn JC, Weller M. Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for imaging of gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0. Eur J Nucl Med Mol Imaging. 2019 Mar;46(3):540-557. doi: 10.1007/s0025 PMID 30519867
• Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, Kaplan RN, Patterson GH, Fry TJ, Orentas RJ, Mackall CL. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015 Jun;21(6):581-90. doi: 10.1038/nm.3838. Epub 2015 May 4. PMID 25939063
• Portnow J, Wang D, Blanchard MS, Tran V, Alizadeh D, Starr R, Dodia R, Chiu V, Brito A, Kilpatrick J, McNamara P, Forman SJ, Badie B, Synold TW, Brown CE. Systemic Anti-PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid. JAMA Oncol. 2020 Dec 1;6(12):1947-1951. doi: 10.1001/jamaoncol.2020.4508. PMID 33030521

Identifiers

NCT: NCT07481721 · NCC5972 · 2024-I2M-3-014

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗