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

Abstract

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.

Keywords: AAV; Adeno-associated virus; Cellular immune response; anti-AAV immunogenicity.

Fig. 1

Representative kinetics of systemic AAV vector administration, immune responses, and AAV gene expression. Each panel shows a representative curve after hypothetical AAV vector administration. The y-axis is expressed in arbitrary units; the x-axis begins at initial vector infusion and spans approximately 75 days. Serum genome copies are expected to decay after infusion. Innate immune responses are expected to peak soon after infusion. Liver enzyme elevation indicating liver damage, if expected, could occur after initial AAV exposure and/or after AAV gene expression and adaptive immune response

Fig. 2

Decision tree for implementation of cellular immunogenicity assays in AAV modality-based gene therapy clinical studies. Strategy is developed using a multi-factorial approach. Evidence of TAb and/or NAb response and immune tolerance status of site/tissue of administration are important factors to consider. Other parameters such as PD, lack of persistence of vector DNA in target tissue, and unexpected safety signals that may suggest evidence of immune-mediated toxicity should be evaluated prior to the decision to conduct assessment of cellular immune response in blood compartment