T-Cell Therapy Might be Good Approach for Glioblastoma: Study

Researchers from the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim (UMM) have achieved a significant breakthrough in the fight against glioblastomas, one of the most aggressive forms of brain tumors. They successfully tested a novel form of cellular immunotherapy in mice, offering hope for improved treatment options for patients suffering from this deadly disease. 

Glioblastomas are notoriously difficult to treat as they spread diffusely within the brain and are often resistant to complete surgical removal, chemotherapy, and radiation therapy. In search of more effective treatments, scientists have been exploring various immunotherapeutic approaches, including adoptive T-cell therapies.

This approach involves isolating a patient’s T cells, modifying them in a laboratory setting, and then reintroducing them into the patient’s body to target the cancer cells. The study was published in Neuro-Oncology. Dr. Lukas Bunse, a scientist at DKFZ and a physician at UMM, pursued a relatively new concept known as “T cell receptor transgenic cells” in his study.

In this approach, patients with brain tumors were first exposed to an antigenic fragment of the NLGN4X protein (Neuroligin4X), which plays a role in synaptic formation. NLGN4X is abundant in glioblastoma cells but nearly absent in healthy brain tissue. 

Following exposure to NLGN4X, the researchers isolated T cells from the patient’s blood that had been activated by this antigen. These T cells carried a T cell receptor that specifically recognized NLGN4X, making them suitable candidates for targeting glioblastoma cells. 

However, obtaining enough NLGN4X-specific T cells through this method proved challenging. To overcome this limitation, the scientists isolated the gene responsible for coding the NLGN4X-specific T cell receptor. Using this gene, they could equip T cells from donor blood or T cell lines in a culture dish with the specific receptor, enabling them to generate many T cells with identical specificity for NLGN4X. 

In subsequent experiments, the researchers demonstrated that these NLGN4X-specific T cells were capable of effectively killing brain tumor cells in a laboratory setting. When they administered these transgenic NLGN4X-specific human T cells to mice with brain tumors, more than 40% of the treated animals responded positively to the treatment. Their tumors shrank, and they survived longer compared to untreated mice. 

These promising results have encouraged Dr. Bunse and his team to believe that T-cell receptors induced by vaccination and targeting brain tumor antigens could represent a valuable approach for developing new immunotherapies against glioblastoma. Similar T-cell receptor transgenic T-cell therapies have already shown success in prolonging the lives of some melanoma patients. 

Notably, the T-cell receptor transgenic cell therapy differs from another established approach known as CAR-T (chimeric antigen receptor) cell therapy, which has received approval for treating various leukaemia’s and lymphomas. One key distinction is that T-cell receptor transgenic cells can target antigens found exclusively inside cancer cells, including those presented on the cell surface through molecules known as MHC class 1. CAR-T cell receptors lack this capability. 

Dr. Michael Platten, director of the Department of Neurology at the University Medical Center Mannheim and a department head at DKFZ, expressed enthusiasm for the future of this research, stating, “We will now work intensively to be able to test this concept in the clinic.” 

This groundbreaking research offers a promising avenue for the development of innovative immunotherapies that could potentially provide new hope and improved outcomes for patients grappling with the devastating diagnosis of glioblastoma. 

Journal Reference 

C Krämer, M Kilian, Y C Chih, A Kourtesakis, D C Hoffmann, T Boschert, P Koopmann, K Sanghvi, A De Roia, S Jung, K Jähne, B Day, L D Shultz, M Ratliff, R Harbottle, E W Green, R Will, W Wick, M Platten, L Bunse, NLGN4X TCR transgenic T cells to treat gliomas, Neuro-Oncology, 2023;, noad172, https://doi.org/10.1093/neuonc/noad172