3 March 2025
Glioblastoma is the most common and aggressive primary malignant brain tumor in adults, with an annual incidence of approximately 3 cases per 100,000 The current standard of care for GBM includes maximum safe surgical resection followed by radiotherapy with concurrent and adjuvant chemotherapy with or without tumor treating fields .
Despite considerable preclinical and clinical efforts aimed at enhancing therapeutic modalities and extending patient survival, a poor prognosis persists for patients, with a median overall survival ranging between12 and 18 months post-diagnosis.
Therefore, novel, innovative therapeutic approaches are urgently needed. Advancements in molecular engineering have facilitated the development of new generations of engineered T cells, expressing synthetic receptors known as chimeric antigen receptors (CARs).
CAR-T Cell Therapy: A Revolutionary Approach to GBM
CAR-T cell therapy involves modifying a patients T cells to express a chimeric antigen receptor, enabling them to identify and destroy cancer cells expressing specific tumor-associated antigens. Unlike traditional treatments, CAR-T therapy provides targeted action against GBM cells while minimizing damage to normal brain tissue.
IL-13 Alpha-Directed Therapy in GBM
In the study by Brown et al, the trial investigates innovative CAR-T approaches to improve the efficacy of immunotherapy in GBM. This study evaluates the safety and effectiveness of CAR-T cells targeting multiple GBM-associated antigens to overcome tumor heterogeneity.
Key findings from this trial highlight:
- The importance of delivering CAR-T cells directly into the tumor to bypass the blood-brain barrier.
- The role of tumor microenvironment modulation to sustain CAR-T cell activity.
In his study patients receiving IL-13Rα2-targeted CAR-T therapy showed notable reductions in tumor size, particularly with locoregional delivery, though challenges such as tumor antigen heterogeneity and immune suppression remain.
This trial which included 65 participants who had exhausted the use of all conventional therapies, showed a median OS of 7.7 to 10.2 months approximately.
The 3 years OS benefit was >20 – 25%. Such results are unheard in relapsed- refractory Glioblastoma.
Interleukin-13 receptor alpha 2 (IL-13Rα2) is an attractive target for CAR-T therapy, as it is highly expressed in GBM but limited in normal brain tissues. Clinical studies, including trials at the City of Hope, have demonstrated promising results.
Key factors for lower side effects
- Localized Delivery: Direct intracranial and intraventricular administration of IL-13Rα2 CAR-T cells led to tumor regression in select patients.
- Immunological Activation: Treatment with IL-13Rα2 CAR-T cells resulted in significant immune activation, including elevated levels of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in CSF only.
- Safety, feasibility, and bioactivity as localized delivery do not have deleterious side effects as those of given therapy intravenously
HER2neu-Directed Therapy: A New Horizon
The HER2 tumor antigen, a receptor tyrosine kinase, is commonly overexpressed in various cancers including approximately 15% of GBMs is a viable target for CAR-T therapy. The HER2neu-directed CAR-T therapy approach has been explored in clinical trials with encouraging outcomes:
- HER2-CAR T-cell Infusions: A dose-escalation trial demonstrated the feasibility and safety of HER2-targeted CAR-T therapy, with a 50% objective response rate among participants.
- Disease Stability and Regression: Some patients experienced partial tumor regression, while others maintained stable disease for extended periods post-treatment. Remaining 30% of patients were doing well for >2 years.
- Minimal Toxicity: Unlike some other CAR-T therapies, HER2-directed CAR-T infusions showed low rates of severe adverse effects, suggesting a favorable safety profile.
Challenges and Future Directions
While CAR-T therapy holds great promise for GBM, several challenges remain:
- Tumor Heterogeneity: GBM exhibits significant variability in antigen expression, necessitating multi-targeted CAR-T strategies.
- Immunosuppressive Tumor Microenvironment: GBM creates a hostile immune landscape that can limit CAR-T cell persistence and efficacy.
- Delivery Limitations: The blood-brain barrier and tumor localization pose challenges to effective CAR-T cell trafficking.
Future strategies may include combinatorial approaches targeting multiple antigens, integration with immune checkpoint inhibitors, and gene editing techniques to enhance CAR-T cell function and longevity.
Conclusion
CAR-T cell therapy is a groundbreaking advancement in GBM treatment, and targeted therapies against IL-13Rα2 and HER2neu demonstrating promising outcomes. While significant hurdles remain, ongoing research continues to refine CAR-T approaches, paving the way for improved survival and quality of life for GBM patients. As the field evolves, personalized immunotherapy strategies hold the potential to revolutionize brain cancer treatment in the coming years.
References
- Neith, K. City of Hope-developed chimeric antigen receptor (CAR) T cell therapy shows clinical activity in patients with aggressive brain tumors in phase 1 trial. News release. March 7, 2024. Accessed March 12,
- Brown CE, Hibbard JC, Alizadeh D. et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. Published online March 7, 2024. doi:10.1038/s41591-024-02875-1
