Quintessential Role of Apheresis in Gene-modified T-cell Therapy

Leukapheresis, the removal of white blood cells from a patient or donor, is a critical step in the manufacturing of gene-modified T-cell therapies. The cell collection step is needed to acquire starting material in order to generate the final cellular product. The collection efficiency of leukapheresis product may be impacted by various factors such as patient disease state, place in treatment protocol, age, pre-apheresis CD3+ cell counts, hematocrit level, and platelet level[1]^,[2]. A thorough understanding of the methods and processes involved in this step can only benefit the patients and biotech companies developing these therapies. As a leading provider of the devices used in cell collection and cell manufacturing workflow, Terumo Blood and Cell Technologies contributed a chapter in the A-Cell project. The A-Cell project is an 11-chapter case study-based approach to integrating Quality by Design principles in Cell-based Therapy CMC programs. The project is published by Alliance for Regenerative Medicine (ARM), and the National Institute for Innovation in Manufacturing Biopharmaceuticals  (NIIMBL). In the chapter, a discussion on qualification and testing of starting material and components, donor eligibility determination, as well as appropriate product testing and characterization for allogeneic cell-based therapy products, is captured.

The chapter covers the technical considerations for optimal leukapheresis. For example, extracorporeal volume (ECV) i.e., the volume of blood that is flowing through the disposable set at any given time during the apheresis procedure, is an important parameter and can greatly impact the patient or donor undergoing apheresis. For procedural safety, ECV is targeted to be below 15% of patient or donor’s total blood volume (TBV).  As a mitigation strategy for anemic or smaller patients, a blood prime of the disposable set would be performed. Another important parameter is anticoagulation. For the cell collection procedure to occur, the patient or donor’s blood needs to be anticoagulated. Acid citrate dextrose formula A (ACD‐A) is the most widely used anticoagulant (AC) for cell collection procedures. Citrate is actively metabolized by the liver quickly and does not significantly impact the circulating blood in patient or donor. However, citrate received during the procedure can cause certain side effects such as hypocalcemia that needs to be actively monitored. The goal of the apheresis procedure is to minimize the side effect while maximizing the cell collection efficiency.

In addition to considerations for extracorporeal volume and anticoagulation management, a vital understanding of patient specific disease states and treatment regimens are necessary.  Certain disease states require certain therapies that potentially need to be stopped or decreased to optimize leukapheresis and ensure functional CD3+ cells for manufacturing  Furthermore, preparing the patient/donor for apheresis by familiarizing them with the process and apheresis team can help reduce anxiety about an unknown procedure.  It also leads to good communication about duration of leukapheresis, decisions about appropriate vascular access, the need for proper hydration and diet as well as understanding of anticoagulation and potential side effects. The better informed a patient/donor is about cellular collection the safer the procedure will be with hopefully optimal results. The chapter also covered donor consideration for allogeneic cell therapy products. 

In recent years, cellular based therapy has been incorporated into the regulatory guidance around donor identification, collection, cell therapy manufacturing, and administration.  This includes country-based guidelines such as the Food and Drug Administration as well as voluntary accreditation groups like the Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee of International Society of Cellular Therapy and the European Society for Blood and Bone Marrow Transplantation. Together these regulatory guidelines help establish effective standard operating procedures and quality management systems to enable safe and effective cellular collection, manufacturing, and infusion for donors and patients.

In summary, the chapter covered technical aspects of the cell collection process, clinical operation considerations, and available regulatory guidance on donor screening and testing. As the cell therapy industry advances, efforts are constantly made on ensuring consistent, robust apheresis processes for clinical manufacturing through standardization of apheresis center training, equipment, and protocols to minimize variation and increase the quality of starting materials, as well as access to a large, diverse, and reli­able donor network. Through process standardization and comprehensive quality management programs, cell therapy manufacturers can help ensure consistent quality of cellular starting material that optimizes and maintains product safety and efficacy, without sacrificing the safety and comfort of the donor and/or patient.

[1] T. Jo et al., Transplantation and Cellular Therapy 28 (2022) 365.e1 - 365.e7 https://doi.org/10.1016/j.jtct.2022.04.013

[2] M. Qayed et al., Cytotherapy 24 (2022) 869 – 878 https://doi.org/10.1016/j.jcyt.2022.05.003