Home Medizin Die innovative CAR-T-Zelltherapie zielt auf zwei Proteine ​​ab, um aggressives Hirntumorwachstum zu bekämpfen

Die innovative CAR-T-Zelltherapie zielt auf zwei Proteine ​​ab, um aggressives Hirntumorwachstum zu bekämpfen

von NFI Redaktion

A recent report published in Nature Medicine presented the first results of patients with recurrent Glioblastoma (rGBM) treated with intrathecally administered autologous bivalent chimeric antigen receptor (CAR) T-cells targeting the epidermal growth factor receptor (EGFR) and Interleukin-13 receptor alpha 2 (IL13Rα2) in a clinical phase-1 study.


Study: Intrathecal bivalent CAR-T cells targeting EGFR and IL13Rα2 in recurrent Glioblastoma: Interim results of the phase-1 trial. Image Source: Gorodenkoff/Shutterstock.com










Study: Intrathecal bivalent CAR-T cells targeting EGFR and IL13Rα2 in recurrent Glioblastoma: Interim results of the phase-1 trial. Image Source: Gorodenkoff/Shutterstock.com

Background

Recurrent GBM is an aggressive, treatment-resistant brain tumor for which there are no conventional treatment options after radiochemotherapy. The median overall survival (OS) is less than a year, indicating an urgent unmet medical need in oncology for effective treatment.

Despite limited treatment options, chimeric antigen receptor T-cells targeting GBM-specific antigens have shown tolerable safety but limited efficacy in adults.

Tumor antigen heterogeneity, intrinsic T-cell dysfunction, and immunosuppressive tumor microenvironments are examples of resistance mechanisms.

About the Report

In the report, researchers describe the efficacy and safety of CART-EGFR-IL13Rα2 cells in treating rGBM patients recruited in an ongoing open phase-1 study.

The researchers included six adults presenting with multifocal and progressive wild-type glioblastoma that recurred after radiotherapy. Exclusions were those who received Bevacizumab within three months before the study start and those with localized central nervous system tumors.

They used immunofluorescence analysis pre-treatment to detect EGFR and IL13Rα2 in brain samples. The data cut-off date was February 2, 2024, with a mean follow-up of 2.5 months.

Three patients received 1 × 107 cells (dose level 1), while the others received 2.5 × 107 cells (dose level 2) between June 14, 2023, and January 2, 2024, 17-35 days post-operation. Primary objectives were safety, maximum tolerated dose, dose-limiting toxicity (DLT), and adverse events.

Secondary objectives included the proportion of treated patients, manufacturing errors, objective response rate (ORR), response duration, overall survival (OS), and progression-free survival (PFS).

The team obtained brain Magnetic Resonance Imaging (MRI) images 24-48 hours post-CAR-T therapy, four weeks later, and monthly thereafter.

They collected cerebrospinal fluid (CSF) at study start, day one, day four, day seven, day 10, day 14, day 21, and day 28 for pharmacokinetic evaluation using quantitative Polymerase Chain Reaction (qPCR).

Cytokine release syndrome (CRS) was assessed following American Society for Transplantation and Cellular Therapy (ASTCT) guidelines, and neurotoxicity was evaluated using Immune effector-associated neurotoxicity syndrome (ICANS) criteria.

Treatment response was assessed following Modified Response Assessment in Neuro-Oncology (mRANO) standards.

Results

The use of CART-EGFR-IL13Rα2 cells in cancer patients was associated with early-onset neurotoxicity, possibly ICANS. All six patients showed reduced tumor size and enhancement, but none met the ORR criteria. Researchers identified CAR-T cell frequency and cytokine release in all patients, with all developing neurotoxicity.

Patient 1 was diagnosed with grade 2 neurotoxicity post-CAR treatment, leading to disorientation, nausea, and aphasia. Anakinra and Dexamethasone improved his neurological status.

Surgically removing a tumor nodule, researchers revealed treatment-related changes and unusual glial cells. The disease progressed after two months, prompting Bevacizumab treatment, and the patient continues to survive with an OS of eight months.

Patient 2 had rapid tumor progression and facial paralysis indicative of grade 3 neurotoxicity. Anakinra and Dexamethasone were administered as treatment. The tumor mass decreased without intervention on day two and showed pseudoprogression. The patient developed hydrocephalus symptoms, refused the shunt, and died five months post CAR-T cell therapy.

Presenting with worsening leptomeningeal disease and decreased performance, Patient 3 developed grade 3 neurotoxicity and received Anakinra and Dexamethasone treatment.

Despite fluctuations in orientation and attention, the patient recovered by day four, returning to baseline neurological status within a week and continues to exhibit stable disease.

Significant neurotoxicity occurred in Patient 4, who received Dexamethasone, Anakinra, and Tocilizumab, leading to improved mental status and restoration of pre-treatment neurological baseline. Enhancement nodes and periventricular nodules in Patient 4 were reduced and remained stable at treatment level 2.0.

Patient 5 developed multifocal tumor progression and grade 2 CAR neurotoxicity, which improved to grade 1 by day three. He experienced increasing fatigue, physical weakness, and loss of appetite. Dramatic tumor load reduction followed a doubling of Dexamethasone dose.

However, the patient returned with increased lethargy, fatigue, and inadequate oral intake. A steroid dose increase at day 28 reduced the severity of multifocal irregular contrast enhancement.

Post CAR-T cell injection, Patient 6 had tumor progression in the left midbrain and severe right-side hemiparesis. He suffered worsening aphasia and increasing weakness on the right side, leading to complete hemiplegia.

Despite Dexamethasone and Anakinra treatment, extensive hemiparesis persisted. As part of his therapy, he received intravenous Bevacizumab.

Initial human data demonstrate the safety and bioactivity of CART-EGFR-IL13Rα2 treatment in individuals with multifocal, treatment-resistant rGBM. The therapy reduced tumor size and enhancement but resulted in early-onset acute neurotoxicity, manageable at both dosages. Results need confirmation through larger sample sizes and longer follow-ups.

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