Positive results from an early clinical study of local radioimmune drug for brain tumors

Tumors with brain metastases often have a poor survival prognosis, including patients with a variety of high-risk pediatric tumors, such as high-risk neuroblastoma. In addition to the currently used surgery, brain radiation and chemotherapy, these patients are in dire need of entirely new therapies to control tumor progression.

B7H3 (CD276) is a glycosylated membrane protein with limited expression in normal tissues but relatively high expression on a variety of adult and pediatric tumors, including brain tumors and brain metastatic tumor cells, making it an important target for antibody therapy. Omburtamab is a murine monoclonal antibody against B7H3 that combines with radioactive I131 to form the targeted radioimmunotherapeutic drug—I131-omburtamab. Previous studies have found that antibody drugs are difficult to cross the blood-brain barrier, but intracerebroventricular injection of radioimmune drugs may be effective in meningeal metastases and reduce systemic toxicity. To explore the safety and efficacy of I131-omburtamab in pediatric tumors, investigators initiated a clinical trial to test drug metabolism, pharmacokinetics, and preliminary efficacy in pediatric tumors with meningeal metastases.

On November 12, 2022, Memorial Sloan Kettering Cancer Center Professor Kim Kramer's team published an article in the Journal of Hematology & Oncology titled "Phase 1 study of intraventricular I131-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies". The paper presents data from a phase 1 clinical study of intraventricular direct 131I-omburtamab radioimmunotherapy in patients with tumors. The study confirmed the overall safety of the therapy, including that it can be used in combination with a number of other approaches in pediatric patients with meningeal metastases. Long-term survival beyond expectations has been observed in some patients, particularly in patients with neuroblastoma brain metastases, with the longest having reached 17 years. If subsequent larger controlled studies can demonstrate the effect, it will hopefully lead to better treatment options for this group of patients.

36 treated patients with high-risk or recurrent brain tumors or brain metastases, including neuroblastoma, ventricular meningioma, and rhabdomyosarcoma, were enrolled in the study and treated with one to two cycles of the radioimmunotherapy drug I131-omburtamab.

Of the 36 patients, 19 received only one cycle of treatment, and reasons for discontinuation included mainly disease progression (12 patients), and long-term myelosuppression (4 patients). The remaining 17 patients received two cycles of treatment with a manageable safety profile, with very few patients developing grade 3 meningitis. Supportive therapy and hormone therapy effectively relieved symptoms.

Radiographic imaging revealed that the drug exhibited good tissue distribution, with significantly higher enrichment concentrations in cerebrospinal fluid than in blood, with median values of 1.01 mGy/MBq and 0.04 mGy/MBq, respectively, a ratio of 24.2. The radioactive intensity in major organs was also significantly lower than the maximum tolerated dose in normal tissue. Interestingly, if patients were previously treated with murine-derived antibodies (e.g., GD2 drugs), then their blood clearance of radioimmune drugs was more rapid, resulting in a higher cerebrospinal fluid/blood ratio, potentially further improving safety and treatment indices.

Although efficacy was not the primary endpoint in this phase 1 clinical study, the investigators observed positive signals in some of the neuroblastoma patients. When radioimmune drugs were used along with other treatment regimens, survival in some patients significantly exceeded historical data. 7 of 15 patients survived 13 to 17 years after treatment, and these 15 patients had a median progression-free survival of 7.5 years and a median overall survival of 11.1 years, with only 13% of patients experiencing a recurrence of brain recurrence. Historically, almost 100% of such patients relapsed, with a median survival of only 6 months. Interestingly, no correlation was found between radioimmune drug dose and survival, suggesting that either low doses of radioimmune drugs are sufficient to produce a better outcome.

This phase 1 clinical study confirmed the safety of ventricular injection of the radioimmune drug I131-omburtamab in pediatric tumor patients with meningeal metastases. The study also found that systemic clearance of the drug in the blood is faster and safety may be higher if neutralizing antibodies against the drug are present in the blood.

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