CAR T-Cell Therapy for glioblastoma
Glioblastoma, short for GBM, represents the most malignant and treatment-refractory of the primary brain tumors. Current improvements in surgery, radiation therapy, and chemotherapy continue to paint a disappointing scenario of patients having an approximate 15 months to survive from their initial diagnosis.
Thus, an even newer direction is currently in high pursuit-the so-called Chimeric Antigen Receptor T-cell treatment.
Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options. CAR T-cell therapy is a revolutionary, universe-changing immunotherapy that genetically engineers the expression of T cells to target GBM-specific antigens such as IL13Rα2, EGFRvIII, and HER2. Although challenging tumor heterogeneity and the immunosuppressive microenvironment are among the challenges to its success, active research is focused on combining therapies and optimizing delivery techniques for better CAR T-cell efficacy, which could be invaluable in improving outcomes for patients with GBM.
Understanding CAR T-Cell Therapy
CAR T-cell therapy takes T cells from a patient and genetically engineers them to express receptors specific for tumor-associated antigens. These engineered cells are then reintroduced into the patient, where they find their target, selectively killing cancer cells expressing that target antigen. This particular therapy has been very effective in hematologic malignancies but, within the setting of solid tumors such as GBM, faces significant challenges.
How CAR T-Cell Therapy Works?
T Cell Collection
- A patient’s white blood cells, including T cells, are extracted through a process called leukapheresis.
Genetic Modification
- The T cells are genetically modified in a lab to express a synthetic receptor called a Chimeric Antigen Receptor (CAR).
- This receptor allows the T cells to recognize and bind to specific antigens found on cancer cells.
Expansion & Quality Testing
- The modified T cells are multiplied in large numbers to ensure a sufficient dose for treatment.
- These cells undergo rigorous testing for quality and safety before being infused back into the patient.
Reinfusion into the Patient
- The CAR T cells are reintroduced into the patient’s bloodstream, where they circulate and seek out cancer cells that express the target antigen.
Cancer Cell Destruction
- Once the CAR T cells recognize and bind to the tumor cells, they activate the immune system to destroy the cancer cells.
- They may also stimulate the production of more immune cells to enhance the response.
Targeting GBM-Specific Antigens
A critical aspect of CAR T-cell therapy for GBM is identifying suitable antigens that are abundantly expressed on tumor cells but minimally present in normal tissues to reduce off-target effects. Several antigens have been investigated:
IL13Rα2: (Interleukin-13 receptor alpha 2) Overexpressed in a significant subset of GBMs, IL13Rα2 has been targeted in early clinical trials. In a study by Brown et al., a patient with recurrent multifocal GBM received IL13Rα2-specific CAR T cells through intracavitary and intraventricular infusions, leading to regression of all intracranial and spinal tumors for 7.5 months. This case highlighted the potential of this approach, though the patient eventually experienced tumor progression at new sites.
EGFRvIII: (A mutant form of epidermal growth factor receptor) A mutant variant of the epidermal growth factor receptor, EGFRvIII is present in approximately 30% of GBMs. O’Rourke et al. conducted a trial where patients with recurrent GBM received EGFRvIII-directed CAR T cells intravenously. The therapy was feasible and safe, with CAR T cells trafficking to the tumor site and mediating antigen loss, though clinical efficacy was limited.
HER2: (Human epidermal growth factor receptor 2) The human epidermal growth factor receptor 2 is another target under investigation. Ahmed et al. treated 17 patients with HER2-specific CAR T cells, observing a median overall survival of 11.1 months from the first T-cell infusion. Notably, three patients exhibited stable disease for over two years.
- GD2 (Disialoganglioside, a surface antigen found in GBM cells)
Studies and References
Let us look at some of the articles, reviews, studies and papers published on leading journals and platforms on CAR T Cell therapy for Glioblastoma.
1) CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges:
The article “CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges” provides an overview of Chimeric Antigen Receptor (CAR) T-cell therapy for the treatment of glioblastoma (GBM), an aggressive brain tumor with few therapeutic options available. Here the authors discuss the problem of targeting GBM due to its heterogeneity and immunosuppressive tumor microenvironment.
They emphasize recent clinical trials targeting antigens such as IL13Rα2, EGFRvIII, and HER2, with both the potential and limitations observed. The review emphasizes the need for innovative approaches to enhance CAR T-cell efficacy. This includes combination therapies to face the possibility of a blood-brain barrier obstruction and addressing heterogeneity in antigens. Finally, the authors conclude that though CAR T-cell therapy holds promise for GBM, many challenges remain before it may be beneficial for patients with this formidable disease.
Reference: CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges.
2. Targets in Glioblastoma
A Systematic Review on Molecular Targets and Treatment Strategies by Agosti et al. (2024) is a review that focuses on the use of CAR T-cell therapy in the treatment of glioblastoma (GBM). The authors analyze various molecular targets, including EGFRvIII, IL13Rα2, HER2, and GD2, discussing their potential efficacy and challenges.
It emphasizes the challenges in GBM treatment; for example, tumor heterogeneity, the immunosuppressive nature of the tumor microenvironment, and the presence of the blood-brain barrier. Moreover, innovative strategies to improve CAR T-cell therapy, for example, by targeting multiple antigens, combinations of therapies, and delivery methods, are discussed. The authors conclude that since CAR T-cell therapy holds promise, much is yet to be done in terms of overcoming these current limitations and better outcomes for patients.
Challenges and Future Directions
Despite these promising findings, several obstacles hinder the widespread success of CAR T-cell therapy in GBM:
Tumor Heterogeneity: GBMs exhibit significant genetic and antigenic diversity, leading to potential escape mechanisms where tumor cells lacking the target antigen survive and proliferate.
Immunosuppressive Microenvironment: The GBM microenvironment can suppress immune activity, diminishing CAR T-cell efficacy.
Delivery Barriers: Efficiently delivering CAR T cells to the tumor site, especially across the blood-brain barrier, remains a significant challenge.
To overcome these hurdles, researchers are exploring strategies such as targeting multiple antigens simultaneously, combining CAR T-cell therapy with immune checkpoint inhibitors, and enhancing CAR T-cell persistence and functionality. A systematic review by Agosti et al. emphasizes the need for innovative delivery methods, combination therapies, and personalized approaches to improve outcomes in GBM patients.
Future Directions
To enhance the success of CAR T-cell therapy for GBM, researchers are exploring:
- Targeting multiple antigens to overcome tumor heterogeneity.
- Combining CAR T therapy with immune checkpoint inhibitors to counteract immunosuppression.
- Improving delivery methods such as direct injection into the brain or using nanoparticles to transport CAR T cells.
What are the advantages of CAR-T Cell Therapy?
CAR T-cell therapy is latest breakthrough in the battle against glioblastoma. Although early clinical trials have demonstrated feasibility and safety, achieving consistent and durable responses requires addressing the complex challenges inherent to GBM. Ongoing research and clinical trials will be pivotal in refining this therapeutic approach, with the ultimate goal of improving survival and quality of life for patients afflicted by this formidable disease.