Immunogenicity of advanced therapy medicinal products: risk factors and mitigation measures

The increasing number of authorized Advanced Therapy Medicinal Products (ATMPs) and those in clinical studies bring forward safety concerns that may be difficult to predict and manage, including host immune responses towards the complex products and their components. Most CAR T products have caused severe immunologically related adverse reactions due to the highly activated T-cells. In addition, viral vectors that have been used both for in vivo and ex vivo gene therapy have shown host immune responses, some being severe and preventing repeated dosing of the product. For cell therapies, off-the-shelf allogeneic products would be the most appealing approach, however, alloreactivity of the cells has thus far hampered the development of many products. Modification of the ATMPs and development of suitable assays may be needed to manage host immune responses of individual products. This review discusses the risk factors related to unwanted immunogenicity of ATMPs, the host response mechanisms, available tools for immunogenicity risk mitigation and provides examples how the immunogenicity aspects have been addressed for the first authorized ATMPs.

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