Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy

The number of approved or investigational late phase viral vector gene therapies (GTx) has been rapidly growing. The adeno-associated virus vector (AAV) technology continues to be the most used GTx platform of choice. The presence of pre-existing anti-AAV immunity has been firmly established and is broadly viewed as a potential deterrent for successful AAV transduction with a possibility of negative impact on clinical efficacy and a connection to adverse events. Recommendations for the evaluation of humoral, including neutralizing and total antibody based, anti-AAV immune response have been presented elsewhere. This manuscript aims to cover considerations related to the assessment of anti-AAV cellular immune response, including review of correlations between humoral and cellular responses, potential value of cellular immunogenicity assessment, and commonly used analytical methodologies and parameters critical for monitoring assay performance. This manuscript was authored by a group of scientists involved in GTx development who represent several pharma and contract research organizations. It is our intent to provide recommendations and guidance to the industry sponsors, academic laboratories, and regulatory agencies working on AAV-based GTx viral vector modalities with the goal of achieving a more consistent approach to anti-AAV cellular immune response assessment.

Automated summary

The number of approved or investigational late phase viral vector gene therapies (GTx) is increasing rapidly, with adeno-associated virus vector (AAV) technology being the most commonly used platform. Pre-existing anti-AAV immunity has been established and is considered a potential barrier for successful AAV transduction, potentially impacting clinical efficacy and adverse events. This manuscript provides recommendations and guidance for the assessment of anti-AAV cellular immune response, including correlations with humoral responses, the value of cellular immunogenicity assessment, and critical parameters for monitoring assay performance.