Immunotherapy for Brain Tumors: Disappointments, New Research, and Hope

Brain tumors are among the most challenging cancers to treat in oncology. One of the most aggressive, glioblastoma multiforme (GBM), is known for its resistance to treatment. Standard approaches combine surgery, radiotherapy, chemotherapy, and electrical-current therapies such as TTF , but these methods are often insufficient to stop GBM progression.

Although innovative approaches such as targeted therapies and immunotherapies have revolutionized care for many cancers, the hoped-for success has not yet been achieved in brain tumors such as GBM. Particularly over the past 20 years, very few new medicines have been approved for GBM and other brain tumors, and no immunotherapy has been approved in this field. This reflects their complex biology and major limitations such as the blood–brain barrier.

Newer generations of immunotherapy are therefore creating fresh hope for treating GBM and other brain tumors.

Immunotherapy for Brain Tumors: Disappointments and Hope

Results from three large phase III studies of nivolumab (Opdivo) in newly diagnosed or recurrent glioblastoma (GBM) have been disappointing in recent years. By contrast, immunotherapy studies in brain metastases are highly encouraging. Phase II trials in patients with asymptomatic melanoma brain metastases have shown objective response rates above 40%.

The Power and Challenges of Immunotherapy in Clinical Trials

Results are particularly promising for brain metastases from other cancers. However, treating symptomatic brain metastases remains difficult, and outcomes in these patients continue to disappoint. Last year, in patients with melanoma-related leptomeningeal (meningeal) metastases , the first phase I clinical trial of intrathecal immune checkpoint inhibitor treatment (nivolumab monotherapy), administered into the cerebrospinal fluid, showed that this form of immunotherapy was both safe and tolerable.

Findings Presented at the ESMO Congress 2024

Early data presented at the ESMO Congress 2024 suggest promising developments for the future of immunotherapy in brain tumors. They highlight how active and open to progress research in this field is.

The congress featured many studies investigating

• immune checkpoint inhibitors,
• viral therapy,
• vaccines,
• cytokine-based therapies, and
• cellular treatments.

mRNA Vaccine

One study assessed an mRNA-based multiepitope vaccine in newly diagnosed glioblastoma patients whose O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status was negative . It examined the safety and dose escalation of a vaccine derived from tumor-associated antigens, an mRNA-based multiepitope vaccine (Abstract 440O). Compared with peptide vaccines, mRNA-based vaccines are easier and faster to manufacture. However, tumor antigens may not be expressed uniformly throughout the tumor, potentially leaving the immune response too weak to overcome the tumor's immunosuppressive microenvironment .

Dendritic Cell Vaccine

Another phase I trial investigated the safety and feasibility of intracranially administered myeloid dendritic cells combined with nivolumab and ipilimumab in patients with recurrent high-grade glioma (Abstract 441O). The results showed that a complex regimen could be delivered successfully, with encouraging survival rates.

CAR-γδ T Cells: A Treatment of the Future?

Allogeneic CAR-γδ T cells represent an exciting development. They recognize a broad range of antigens and can be administered independently of MHC molecules. In a phase I trial of allogeneic CAR-γδ T cells in patients with B7H3-positive recurrent glioblastoma, a 43% partial response rate and 57% stable disease were observed (Abstract 4420). The cells also showed excellent persistence and a favorable safety profile. However, their recognition of a very broad antigen range may carry potential adverse effects, and longer follow-up is required to establish whether this approach is a viable option for treating brain tumors.

Conclusion and Future Expectations

Immunotherapy holds significant potential in brain tumor treatment, and we hope to see revolutionary advances in the coming years. As with other solid tumors, the day when immunotherapy brings a major revolution to brain tumor treatment is approaching.

Immunotherapy's importance in brain tumor treatment is growing, and these strategies may open the door to a new era in cancer care.