Repeated Injections Double Progression-Free Survival in Glioblastoma

People with newly diagnosed glioblastoma who received repeated injections of genetically modified immune cells directly into the brain experienced double the progression-free survival compared with those who received a single injection, according to results from a phase I clinical trial published in the Journal of Clinical Oncology.

Patients who received multiple doses had a median progression-free survival of 16.1 months, compared with 8 months for those who received only one dose.

The investigational therapy — called drug-resistant immunotherapy, or DRI — uses a type of immune cell known as gamma-delta T cells that are collected from the patient, genetically modified in a laboratory to resist the chemotherapy drug temozolomide and then delivered directly into the tumor cavity through a small tube placed in the brain during surgery.

What the Study Found: Survival Outcomes for People With Glioblastoma

Among the 13 people who received the DRI therapy, the median progression-free survival across all patients was 9.9 months. People who received a single dose had a median progression-free survival of 8 months, while those who received repeated doses had a median progression-free survival of 16.1 months.

The median overall survival for all treated patients was 15.6 months, with a range of 5 to 51 months. Among people who received a single dose, median overall survival was also 15.6 months (range, 9 to 18 months). In people who received repeated doses, median overall survival was 19.5 months (range, 5 to 51 months), and several patients remained alive and progression-free at the time of data cutoff.

Researchers also noted what appeared to be a dose-related improvement in immune cell recovery during the treatment period. People who received more doses showed more robust and sustained recovery of T cells and natural killer cells in their bloodstream, even while receiving chemotherapy known to reduce immune cell counts.

How the Glioblastoma Immune Cell Trial Was Designed

The trial (NCT04165941) used a modified 3+3 frequency-escalation design, meaning researchers increased the number of doses — not the number of cells per dose — across three groups while keeping the cell quantity constant at 1 × 10⁷ DRI cells per injection. Patients in Cohort 1 received one dose, those in Cohort 2 received up to three doses and those in Cohort 3 received up to six doses.

Of the 23 people assessed for eligibility, 13 received the therapy. Among those, 62% were male, with a median age of 66 years (range, 21 to 75 years). IDH wild-type tumors were present in 92% of patients, 54% had MGMT-unmethylated tumors and 46% underwent subtotal resection.

The treatment process began at the time of surgery, when a small catheter called a Rickham catheter was placed into the tumor cavity. Several weeks later — to allow the immune system to recover from surgery — patients underwent apheresis, a procedure to collect their own immune cells. Those cells were then genetically modified in a bioreactor with an MGMT-expressing gene, giving them the ability to survive in the presence of temozolomide, and stored until needed.

On the first day of each maintenance chemotherapy cycle, patients received 150 mg/m² of temozolomide intravenously. Within four hours, the modified DRI cells were thawed and injected through the catheter directly into the tumor cavity. Patients were observed in an outpatient clinic before being discharged, then continued oral temozolomide for four additional days to complete the cycle.

Five patients did not receive the therapy because their manufactured cells did not meet release criteria. Four patients withdrew consent and one did not complete chemotherapy and radiation therapy. The single-center trial was funded by IN8bio, Inc.

Side Effects Observed in the Glioblastoma Immune Cell Trial

No dose-limiting side effects were observed in any of the three cohorts, and no cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were reported at any point during the study.

Eleven serious side effects were reported overall. Most were grade 3 events attributed to standard chemotherapy and radiation, not to the DRI cells. Two patients died of causes unrelated to the investigational therapy — one from a cardiac event and one from a systemic infection. There were no treatment-related deaths. No patients developed infections at the catheter site, and imaging showed no signs of inflammation or encephalitic changes.

Grade 3 side effects included decreased platelet count (15.4%), decreased white blood cell count (7.7%), decreased lymphocyte count (7.7%), deep vein thrombosis (7.7%), hypertension (7.7%), hypotension (7.7%), dysarthria (7.7%) and hydrocephalus (7.7%). Grade 4 side effects included decreased neutrophil count (7.7%) and pulmonary embolism (7.7%).

Blood samples from all patients were tested for replication-competent lentivirus — a standard safety measure for gene-based therapies — at multiple time points up to 365 days after the first treatment. All results were negative. Analysis of serum proteins showed no meaningful increases in inflammatory markers, including those associated with cytokine release syndrome, after the DRI cells were administered.

References

1. "Intracranial Injection of Investigational Ex Vivo Expanded and Activated Gamma-Delta T Cells Engineered With a Methylguanine-DNA Methyltransferase–Expressing Lentivector in Patients With Primary Glioblastoma" by Dr. Louis B. Nabors, et al., Journal of Clinical Oncology.

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