Antibody-drug conjugates for primary brain tumors

Antibody-drug conjugates (ADCs) enable targeted delivery of cytotoxic or immunomodulatory payloads to cancer cells while relatively sparing healthy tissues. Interest in using ADCs for the treatment of primary brain tumors is growing, as these are frequently infiltrative with tumor cells coexisting with healthy glial and neural tissue. Emerging clinical and translational data from studies of ADCs in primary brain tumors and brain metastases provide evidence of blood-brain barrier penetration and intracranial anti-tumor activity. Proteomic and transcriptomic profiling methods, including RNA sequencing and immunohistochemistry have uncovered clinically actionable ADC targets in primary brain tumors that are not detected by DNA-based next-generation sequencing alone. These targets (HER2, TROP2, FOLR1, CLDN6, HER3, B7-H3) are expressed across both common tumor types (gliomas, meningioma) and rare primary brain tumors (ependymoma, craniopharyngioma, atypical teratoid/rhabdoid tumors). Leveraging label-extension strategies, ADCs already approved for systemic cancers may be rapidly evaluated and translated into neuro-oncology practice. Here we summarize the current evidence supporting ADC use in primary brain tumors and highlight key challenges and future directions for the further development of this therapeutic approach in neuro-oncology.