Diffuse glioma is a malignant primary tumor with multiple growths and extensive infiltration throughout the brain parenchyma (Villa et al., 2018). Complete neurosurgical resection is not possible that leads to recurrence (Ammendola et al., 2023) and/or malignant progression (Cancer Genome Atlas Research, et al., 2015) after surgery. The fifth edition (2021) of the World Health Organization (WHO) classification of central nervous system (CNS) tumors updates the adult-type diffuse glioma classification (Fig. 1), the "glioblastoma" designation is now reserved for IDH wild-type tumors, while astrocyte mutant tumors with histologic features (microvascular proliferation and/or necrosis) are classified as IDH mutant astrocytomas. This change is due to the fact that IDH wild-type diffuse astrocytomas and IDH mutant astrocytomas have fundamentally different biological characteristics and different aggressive disease course. This review emphasizes grade 4 glioblastoma (described as glioblastoma in the references, but with some deviation from the fifth edition of the WHO classification of CNS tumors as glioblastoma), which is highly heterogeneous, aggressive, with severe and extensive angiogenesis (Furnari et al., 2007) leading to poor prognosis. Stupp et al. (Hegi et al., 2005) conducted a milestone trial in 2005, the results showed a survival benefit from the addition of temozolomide (TMZ) to radiotherapy, with a reported median survival of 14.6 months. The patients with MGMT promoter methylation treated with TMZ with a median survival of 21.7 months. Thereafter, the standard treatment procedure for GBM is surgical resection followed by radiation and/or chemotherapy with the alkylating agent TMZ (Chinot et al., 2014). Survival rates for GBM are lower than for all other brain tumors, with a median overall survival (mOS) of 24–44 weeks (Cloughesy et al., 2019) for recurrent glioblastoma (rGBM). There is an urgent need to develop more effective treatments with less toxic to normal brain tissue.

Antibody-drug conjugate (ADC) therapies consist of three elements: targeted antibodies, linkers, and cytotoxic payloads. Based on the specificity of the targeted antibody, this strategy can directly transmit the payload to tumor cells. The emergence of new formulations for ADCs and the encouraging activity in patients with other solid tumors (such as that observed with T-DM1 in breast cancer patients) (Verma et al., 2012) has gained interest in the application of ADCs for the treatment of GBM.

Depending on the payloads, ADCs can be classified as cytotoxic ADCs, immunotoxins with a bacterial toxin payload or radioimmunotherapies with a radioactive isotope payload. The mechanism of action (Fig. 2) of cytotoxic ADCs and immunotoxins is as follows: monoclonal antibodies act as a transport system to carry the payload to the tumor cells expressing the target antigen, and the Fab portion of the antibody bind to the target antigen. Once binding, the antibody linked to the cleavable linker releases the payload into or around the tumor cell, where the cleavage mechanism may occur at an early or late stage of endonucleosome without progressing to the period of lysosomal trafficking (Chau et al., 2019). While the antibody linked to the non-cleavable linker binds to the target antigen, the endocytic process begins and leads to early formation of endonucleosomes, most of which fuse with lysosomes, and then the antibody portion of the ADC undergoes degradation in an acidic and protein hydrolase-rich environment leading to intracellular release of toxins (Rock et al., 2015, Xu, 2015). Depending on the hydrophobicity of the cytotoxic load, the toxic payload may also reach neighboring tumor cells and surrounding stromal tissue by diffusion that leads to a bystander effect resulting in the death of neighboring target-negative cells (Li et al., 2016). Notably, a small fraction of ADC binds to the neonatal Fc receptor (FcRn) at the intranuclear body and returns to the extracellular environment (Chau, 2019). This recycling mechanism can increase the half-life of the antibody and provide protection in case of misdelivery to normal cells. However, excessive recycling of cancer cells may also lead to drug resistance. Radioimmunotherapy can target cell surface receptors (e.g. EGFR) or extracellular targets, such as tenascin, and subsequently leads to structural cellular damage, such as DNA and mitochondria.

In this review, we summarize the results of GBM patients treated with adjuvant ADCs in clinical trials. Compared to similar excellent reviews a few years ago (Gan et al., 2017), we have supplemented and updated clinical data on ADCs used for the treatment of GBM. Compared to similar excellent reviews in recent years (Mair et al., 2023, Parakh et al., 2021), we have conducted statistical analysis of the patient situation in each clinical trial and paid special attention to the administration methods of ADCs, especially the convection-enhanced drug delivery (CED) administration, as these are factors that affect patient survival outcomes. Finally, we propose new strategies for the future treatment of GBM patients with ADC.