Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial

Area of Science:

• Pediatric Oncology
• Immunotherapy
• Cellular Therapy

Background:

• Central nervous system (CNS) tumors are the leading cause of cancer-related death in children.
• Tumor-associated antigens (TAAs) WT1, PRAME, and survivin are frequently expressed in pediatric CNS tumors.
• A novel approach involves using autologous, non-genetically engineered T cells to target these intracellular TAAs.

Purpose of the Study:

• To assess the safety and feasibility of systemically administered, autologous trivalent T cells targeting WT1, PRAME, and survivin in children with CNS tumors.
• To determine the maximum tolerated dose (MTD) of this T-cell therapy.
• To explore preliminary efficacy and immunobiological correlates of the treatment.

Main Methods:

• ReMIND study: an open-label, phase 1 adaptive dose-finding trial.
• Patients with newly diagnosed diffuse intrinsic pontine glioma (arm A) or relapsed/recurrent nonbrainstem CNS malignancies (arms B/C) were enrolled.
• Treated with autologous trivalent T cells targeting WT1, PRAME, and survivin, with or without lymphodepletion.

Main Results:

• Dose level 3 (8 × 10^7 cells/m^2/dose) was established as the MTD.
• The treatment was generally well-tolerated; fatigue and headache were the most common adverse events.
• One dose-limiting toxicity (Grade 5 event) occurred in a patient with diffuse intrinsic pontine glioma.
• Median overall survival in arm A was 13.7 months; median progression-free survival in arms B/C was 5.0 months.
• Three patients in arms B/C achieved long-term survival without further treatment, including one complete response.

Conclusions:

• Autologous trivalent T-cell therapy targeting WT1, PRAME, and survivin is safe and feasible in children with CNS tumors.
• The study met its primary safety and feasibility endpoints, with preliminary efficacy signals observed.
• Further investigation of this immunotherapy for pediatric CNS malignancies is warranted.