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Antibody Drug Conjugates in Glioblastoma - Is There a Future for Them?
Sagun Parakh1,2,3, Joseph Nicolazzo4, Andrew M Scott2,3,5,6
1Department of Medical Oncology, Austin Hospital, Heidelberg, VIC, Australia.
Abstract:
Glioblastoma (GBM) is an aggressive and fatal malignancy that despite decades of trials has limited therapeutic options. Antibody drug conjugates (ADCs) are composed of a monoclonal antibody which specifically recognizes a cellular surface antigen linked to a cytotoxic payload. ADCs have demonstrated superior efficacy and/or reduced toxicity in a range of haematological and solid tumors resulting in nine ADCs receiving regulatory approval. ADCs have also been explored in patients with brain tumours but with limited success to date. While earlier generations ADCs in glioma patients have had limited success and high toxicity, newer and improved ADCs characterised by low immunogenicity and more effective payloads have shown promise in a range of tumour types. These newer ADCs have also been tested in glioma patients, however, with mixed results. Factors affecting the effectiveness of ADCs to target the CNS include the blood brain barrier which acts as a physical and biochemical barrier, the pro-cancerogenic and immunosuppressive tumor microenvironment and tumour characteristics like tumour volume and antigen expression. In this paper we review the data regarding the ongoing the development of ADCs in glioma patients as well as potential strategies to overcome these barriers to maximise their therapeutic potential.
Insights
Antibody drug conjugates (ADCs) show promise for glioblastoma (GBM) treatment. Newer ADCs offer improved efficacy and reduced toxicity, but challenges like the blood-brain barrier must be overcome for better therapeutic potential in brain tumors.
Area of Science:
- Neuro-oncology
- Pharmacology
- Cancer Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Antibody drug conjugates (ADCs) are emerging therapeutics combining targeted antibody delivery with cytotoxic payloads.
- Previous ADC trials in glioma patients yielded limited success and significant toxicity.
Purpose of the Study:
- To review the current development of ADCs for glioma treatment.
- To identify challenges hindering ADC efficacy in the central nervous system (CNS).
- To explore strategies for overcoming these barriers and maximizing therapeutic potential.
Main Methods:
- Literature review of ongoing ADC development in glioma.
- Analysis of factors affecting ADC delivery and efficacy in the CNS.
- Examination of strategies to enhance ADC therapeutic potential.
Main Results:
- Newer ADCs demonstrate improved characteristics, including lower immunogenicity and more potent payloads.
- Despite promise in other cancers, ADC efficacy in glioma remains mixed.
- Key challenges include the blood-brain barrier, the tumor microenvironment, and tumor-specific characteristics.
Conclusions:
- Despite challenges, ongoing research and strategic approaches may improve ADC effectiveness in treating gliomas.
- Further investigation into overcoming CNS-specific barriers is crucial for successful ADC-based glioblastoma therapy.
- Optimizing ADC design and delivery strategies holds potential for advancing glioblastoma treatment.
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