April 23, 2024

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Dual-target CAR-T Therapy Shows Promise in Treating Deadly Brain Tumors

Dual-target CAR-T Therapy Shows Promise in Treating Deadly Brain Tumors



Dual-target CAR-T Therapy Shows Promise in Treating Deadly Brain Tumors

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, with patients typically surviving only 12-18 months after diagnosis. Despite decades of research, there is currently no cure for GBM, and approved treatments like surgery, radiation, and chemotherapy have limited effectiveness in extending patients’ lives.

Even with aggressive treatment, most GBM patients will still experience recurrence, with those suffering from recurrent GBM (rGBM) surviving less than a year on average. There are currently no specific treatment interventions proven to extend the survival of rGBM patients. Therefore, effective treatment for recurrent GBM remains one of the greatest unmet medical needs in oncology.

CAR-T cell therapy utilizes the patient’s immune system to combat cancer. To create CAR-T cells, T cells are extracted from the patient and reprogrammed to recognize specific cancer-associated antigens, before being reinfused into the body to seek out, identify, and destroy cancer cells. Currently, CAR-T cell therapy has been FDA-approved for treating various blood cancers, and researchers have been working on designing CAR-T cells to target and kill the solid tumors that constitute the majority of cancer types and numbers. However, breakthroughs have been elusive due to the immunosuppressive microenvironment of solid tumors, tumor heterogeneity, T cell exhaustion, among other reasons.

On March 13, 2024, researchers at the Perelman School of Medicine at the University of Pennsylvania published a study in the journal Nature Medicine titled “Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.”

Dual-target CAR-T Therapy Shows Promise in Treating Deadly Brain Tumors

The early results of this ongoing phase 1 clinical trial suggest that dual-target CAR-T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2) may be an effective strategy for reducing solid tumor growth in the brains of patients with recurrent GBM.

Dr. Stephen Bagley, the first author and co-corresponding author of the paper, stated that this is the first application of dual-target CAR-T cell therapy in the clinical treatment of GBM patients. The preliminary clinical results indicate a step in the right direction, suggesting that delivering CAR-T cells intrathecally into the cerebrospinal fluid of patients may be a key to developing a therapy to overcome the complex defensive systems of GBM.

In this study, the research team developed a dual-target CAR-T cell therapy targeting two common proteins in GBM, EGFR and IL13Rα2 – CART-EGFR-IL3Rα2 cell therapy. EGFR epitopes are present on the surface of tumors in 50%-60% of GBM patients, while IL13Rα2 is expressed in 50-75% of GBM patients and has been shown to be a potential therapeutic target.

Several CAR-T cell therapies approved for market use have been administered intravenously to treat blood cancers. In this study, the research team delivered CAR-T cells intrathecally into the cerebrospinal fluid, allowing them to more directly reach brain tumors.

This ongoing trial is a single-center, open-label, phase 1 clinical study conducted in adult patients with recurrent GBM. The primary endpoint is to evaluate the safety of the therapy, including adverse events and serious adverse events, and to determine the maximum tolerated dose of CART-EGFR-IL3Rα2 cell therapy. As a secondary endpoint, the trial also evaluates objective response rate (ORR), response duration, and overall survival.

The paper outlines mid-term analysis data from the first six patients treated at two different dose levels (1×107 cells, 2.5×107 cells). The first patient was treated in June 2023, and the sixth patient was treated in January 2024. The median follow-up time was 2.5 months (1-7.5 months).

The results showed that MRI scans performed 24-48 hours after dual-target CAR-T therapy demonstrated a reduction in brain tumor size in all six patients, and these reductions persisted for several months in some patients.

The research team stated that although the sample size of this study is small and the follow-up time relatively short, CART-EGFR-IL13Rα2 cell therapy reduced the progression of multifocal refractory recurrent GBM and reduced tumor size. While no patients met the criteria for objective response, three out of the six patients had at least a 30% reduction in tumor size, and three out of the four patients with follow-up times exceeding 2 months maintained a stable disease state.

Professor Donald O’Rourke, the corresponding author, stated that they are encouraged by these results and eager to continue this clinical trial to better understand how this dual-target CAR-T cell therapy affects a broader range of patients with recurrent GBM. Since this cancer is unique in each patient, including a broader range of patients will help determine the optimal dose, better understand neurotoxicity, and more firmly establish treatment effects.

One of the main challenges of CAR-T cell therapy is neurotoxicity, especially when it is delivered to the brain. Neurotoxicity occurs when toxic substances alter the activity of the nervous system, leading to damage or death of neurons. In this clinical trial, all six patients treated experienced severe neurotoxicity, which was controlled with dexamethasone and anakinra (IL1R antagonist) treatment.

Overall, these human clinical trial data demonstrate the preliminary safety and biological activity of dual-target CAR-T cell therapy – CART-EGFR-IL13Rα2 in patients with recurrent GBM. Encouraging early signs of efficacy have been detected, requiring confirmation in more patients and longer follow-up times.

Dual-target CAR-T Therapy Shows Promise in Treating Deadly Brain Tumors

(source:internet, reference only)


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