Innovative CAR T cell therapy targets two proteins to combat aggressive brain tumor growth

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In a recent report published in Nature Medicine, researchers presented the initial results of recurrent glioblastoma (rGBM) patients treated with intrathecally administered, autologous, bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2) in a phase 1 clinical trial.

Study: Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Image Credit: Gorodenkoff/Shutterstock.comStudy: Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Image Credit: Gorodenkoff/Shutterstock.com

Background

Recurrent GBM is an aggressive, treatment-resistant brain cancer with no conventional therapeutic options after chemoradiotherapy. The median overall survival (OS) is less than one year, indicating that effective treatment is an urgent unmet medical need in oncology.

Despite limited therapy options, chimeric antigen receptor T cells that target GBM-specific antigens have demonstrated tolerable safety but poor effectiveness in adults.

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

About the report

In the present report, researchers describe CART-EGFR-IL13Rα2 cell efficacy and safety in treating rGBM patients recruited in an ongoing, open-label, phase 1 trial.

The researchers included six adults presenting with multifocal and progressive wild-type glioblastoma recurring after radiotherapy, excluding those who received bevacizumab within three months before trial initiation and those with localized central nervous system tumors.

They used pre-treatment immunofluorescence analysis to detect EGFR and IL13Rα2 in brain samples. The data cutoff date was February 2, 2024, with a median 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) 17–35 days following surgery between June 14, 2023, and January 2, 2024. The primary objectives were safety, maximum tolerated dosage, dose-limiting toxicity (DLT), and adverse events.

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

The team obtained brain magnetic resonance imaging (MRI) images 24 to 48 hours after CAR T therapy, four weeks later, and monthly afterward.

They collected cerebrospinal fluid (CSF) at baseline and on day one, day four, day seven, day 10, day 14, day 21, and day 28 for pharmacokinetic evaluation by quantitative polymerase chain reaction (qPCR).

They rated cytokine release syndrome (CRS) according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines and neurotoxicity using the immune effector-associated neurotoxicity syndrome (ICANS) criteria.

They assessed treatment response using the 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, perhaps ICANS. All six patients showed reduced tumor size and enhancement, but none satisfied the ORR criteria. The researchers identified CAR T cell abundance and cytokine release in all patients and all developed neurotoxicity.

Patient 1 was diagnosed with grade 2 neurotoxicity following CAR treatment, resulting in disorientation, nausea, and aphasia. Anakinra and dexamethasone improved his neurological condition.

The researchers surgically removed a tumor nodule, revealing therapy-related alterations and uncommon glial cells. After two months, the disease progressed, for which the patient received bevacizumab and continues to remain alive with an eight-month OS.

Patient 2 had rapid tumor development and facial paralysis, which indicated grade 3 neurotoxicity. The team administered anakinra and dexamethasone as treatments. On day two, the tumor mass decreased without intervention, showing pseudo-progression. The patient developed hydrocephalus symptoms, denied shunting, and died five months after receiving CAR T cell therapy.

Patient 3, presenting with deteriorating leptomeningeal illness and decreased performance, developed grade 3 neurotoxicity and received anakinra and dexamethasone treatment.

Despite fluctuations in orientation and alertness, the patient recovered on day four, reverted to his pre-treatment neurological baseline within a week, and continues to have stable disease.

Patient 4 experienced significant neurotoxicity and received dexamethasone, anakinra, and tocilizumab, resulting in a better mental state and a restoration to the pre-treatment neurological baseline. Patient 4's enhancement foci and periventricular nodules were decreased at treatment level 2.0 and remained stable.

Patient 5 developed multifocal tumor progression and grade 2 CAR neurotoxicity, which improved to grade 1 on the third day. He developed increased weariness, physical weakness, and anorexia. The tumor burden decreased dramatically following a doubling of dexamethasone dosage.

However, the patient returned with more lethargy, fatigue, and inadequate oral intake. On day 28, raising the steroid dosage reduced the severity of multifocal irregular enhancement.

Following a CAR T cellular injection, Patient 6 had tumor development in the left midbrain and severe right-sided hemiparesis. He experienced deteriorating aphasia and increased right-sided weakness, resulting in total hemiplegia.

Despite treatment with dexamethasone and anakinra, extensive hemiparesis remained. He got bevacizumab intravenously as part of his therapy.

The first-in-human data demonstrates the safety and bioactivity of CART-EGFR-IL13Rα2 treatment in individuals with multifocal, treatment-resistant rGBM.

The therapy decreased tumor size and enhancement but resulted in early-onset acute neurotoxicity, controllable at both dosages. The findings require confirmation with larger sample sizes and longer follow-ups.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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