The clinical toxicity of advanced therapy medicinal products

Abstract

Aims: Advanced Therapy Medicinal Products (ATMPs) use genes, tissues or cells to offer transformative treatments for a range of diseases. They are associated with different safety challenges when compared to established therapeutics, such as small chemical entities or monoclonal antibodies, due to immunogenicity, off-target effects and organ-specific toxicities. This review evaluates the current clinical evidence on ATMP toxicity, highlighting key mechanisms of toxicity and describing approaches to risk management. Methods: A scoping review was conducted using the MEDLINE and Embase databases to identify studies reporting toxicities associated with gene therapy medicinal products (GTMPs), somatic-cell therapy medicinal products, tissue-engineered products and combined ATMPs. Data were extracted and collated qualitatively, focusing on acute and chronic clinical toxicity. Results: Acute toxicity, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were most often reported in GTMPs, particularly chimeric antigen receptor T-cell therapies. Chronic risks of GTMPs include genotoxicity and tumorigenicity, especially with high-dose adeno-associated virus-based therapies. Somatic-cell therapy medicinal products carry risks of immunological toxicity and tumour formation, particularly in stem cell-based approaches. Tissue-engineered products present challenges of biocompatibility, scaffold degradation and host integration. Management strategies to mitigate anticipated toxicity include preconditioning regimens, safer vector design, immunosuppressive therapies (e.g. tocilizumab) and long-term monitoring. Conclusion: ATMPs offer significant therapeutic promise but require robust safety assessments and proactive risk management plans to address their complex potential toxicity profiles. Personalized approaches, advanced preclinical models and stringent regulatory oversight are essential to ensure these therapies fulfil their potential without compromising patient safety.