New Dual-Target CAR T-Cell Therapy for Recurrent Glioblastoma (GMB)

Immunotherapies are among the most promising treatment options for cancer. In immunotherapy, the patient's own immune system is activated against the tumor, enabling these cells to fight cancer more effectively. Because the treatment indirectly attacks our cancer cells through our own immune system, its side effects are fewer than those of chemotherapy. We know that immunotherapy is now used to treat many types of cancer and that positive results have been achieved.

Amid all these advances, one cancer type in which progress has been slowest is brain cancer. Glioblastoma, a high-grade brain cancer, is one of the most aggressive cancers in adults. With survival generally ranging from 12-18 months, the need for effective treatment options is substantial. Although surgery, radiotherapy, and chemotherapy are used for this disease, their effects are very limited. Glioblastomas (GBM) carry a high risk of recurrence despite the most aggressive treatments.

A Living Drug for Glioblastoma

For such a challenging disease, exciting clinical trial results were published on 13 March 2024 in Nature Medicine. The phase-1 trial involved 6 patients. This study used an immunotherapy treatment, CAR T cells, for GBM.

In this study, the patient's immune-system T cells were collected, modified to attack 2 gene-product receptors involved in tumor growth, and injected back into the patient.

The CAR T cells were modified to target epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Ra2) and were administered intrathecally (into the cerebrospinal fluid through the lower back).

This treatment was named CART-EGFR-IL13Rα2 cells.

EGFR is found on the tumor surface in 50-75% of glioblastoma patients. This is a substantial proportion when considering tumor heterogeneity, meaning the extent to which healthy and cancerous cells around the tumor are mixed.

Tumor heterogeneity is one of the characteristics that most adversely affects brain cancer treatments. Drugs, particularly immunotherapies, cannot effectively identify cancerous cells in this mixed environment, greatly reducing treatment effectiveness.

Another particularly difficult obstacle in brain cancer is the blood-brain barrier. This barrier prevents toxic and disease-causing substances from entering the brain. However, because it also prevents externally administered drugs from reaching the brain, treatments may be ineffective. The blood-brain barrier and tumor heterogeneity are the two main obstacles behind the slow pace of progress in brain cancer.

The primary aim of this study was to determine side effects and the maximum tolerated dose. Secondary aims were to determine the frequency of manufacturing failures and the objective radiological response to treatment.

For this purpose, patients with recurrent, progressive, multifocal glioblastoma were enrolled: 6 patients received this newly developed treatment between 14 June 2023 and 4 January 2024. Their tumors were EGFR-positive and did not have an IDH mutation.

These patients were divided into 2 groups of three. After surgical removal of the recurrent GBM tumor, the 2 groups received different doses of modified CAR T cells. Repeat surgery was performed to reduce the tumor burden.

Patients remained in hospital for a minimum of 7 days after cell administration. During this period, investigators assessed whether observed side effects were caused by the treatment or the tumor.

Within the first 24 hours after treatment began, one patient developed cognitive impairment and became difficult to rouse with verbal stimulation. The patient was therefore transferred to intensive care. Mental status began to improve on day 4. With supportive treatment, the patient returned to the pretreatment neurological condition on day 7.

In addition, tumor regression was observed in every patient 1-2 days after CAR T-cell administration. In a subset of cases assessed later, partial tumor regression was maintained beyond 28 days. However, these findings were insufficient for treatment-response assessment.

An impressive aspect of the study was that tumor growth was evident at the cellular level in all patients, making it possible to observe the effectiveness of CAR T-cell therapy over a short period.

Brain MRI scans after 2 months showed continued tumor regression despite no intervention during this period.

The study also observed more CAR cells in the body than in previous trials. Their peak counts were similar to those in hematological cancers also treated with CAR T cells. The administered cells were subsequently detected in patients' peripheral blood as well. This demonstrated communication between the cerebrospinal fluid and the peripheral circulation: the treatment had crossed the blood-brain barrier. No difference in side effects was observed between the 2 doses. Neither of the 2 doses produced high-grade toxicity, and many observed side effects were attributed to the tumor and its location rather than the treatment.

Conclusion

In conclusion, although a meaningful response for treatment-response assessment could not be established in such an aggressive, rapidly growing cancer, tumor progression was reversed, and this effect was still observable in month 2. The treatment's long-term effectiveness and effect on overall survival remain uncertain. It is important to remember that this treatment was studied in only 6 people. Studies involving more participants are needed to better understand treatment toxicity, determine the ideal dose, obtain more specific findings and clearer short- and long-term results, and establish whether the disease recurs.

Tumor tissue analyses before and after treatment are needed to understand CAR T cells' effects on the tumor microenvironment and infiltration (the spread of cancer cells into surrounding tissues). More detailed investigations of CAR T-cell effects and their relationship with GBM are ongoing. This study offers hope for the future and suggests that effective treatments for brain cancer may be possible.