Bioprocess solutions to assess clinical biodistribution in cell/gene therapies

Abstract

Background & Aim Lack of comprehensive product knowledge in clinical applications may result in toxicity or reduced drug efficacy. The distributive fate and retention of cell/gene therapies is rarely evaluated, with very few studies assessing their biodistribution in a clinical setting. Understanding the location and retention of cells can result in more efficacious and safe treatment, with information facilitating optimisation of dosing strategies, and a greater understanding of the mechanism of action leading to accelerated drug development. Consequently, the TACTICAL phase I/II clinical trial (NCT03298763) will use 89Zr-oxine labelled genetically modified MSCs to visualise and quantify cell biodistribution in metastatic non-small cell lung carcinoma (NSCLC) patients. Methods, Results & Conclusion There are numerous bioprocessing challenges associated with the use and handling of radioactive labels in GMP manufacture, which must be solved without compromising the drug product. These challenges are broadly divided into three categories: operator protection, product integrity, and control of product flow. Each challenge elicits precise design specifications upon the bioprocess, which must be achieved in order to meet product approval against local procedures and current legislation. One such challenge is the necessity for lead shielding to be used throughout manufacture so that operators’ exposure to radiation is kept to a minimum. The subsequent control of material transfer and restricted manufacture footprint (which is needed to operate within the shielding) may lead to the removal of existing equipment and manual transfer operations. The choice of downstream process unit operations must balance material carry-over (i.e. unbound radiolabel, DMSO from cryopreserved products etc.), cell viability, yield and throughput, with the implementation of continuous shielding. Selection of equipment must mitigate manual steps that involve physical contact within close proximity to the product or fluidic pathway, as well as larger equipment (such as centrifuges) which may not fit within a shielded isolator. Bioprocess solutions must involve a considered and complete approach, which thematically address material transfer/fluid flow, biological impact, and ergonomic and operating footprint limitations. An integrated approach between medical physicists, process engineers and clinicians should be strived for, to ensure safety and efficiency of the clinical study is ensured.