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Dalip Sethi, Ph.D., Commercial Leader, Cell Therapy Technologies and Joy Duemke, Director of Marketing, North America, at Terumo Blood and Cell Technologies.
Until recently, even within the biopharma sphere, most people have not thought about blood in the context of therapeutic interventions. However, recent technological advances have forced a rethink about the therapeutic role blood plays well beyond transfusion.
This new focus has largely been spurred by the progress of cell and gene therapies (CGTs), which are underpinned by blood products derived from donors and patients themselves. Efficient development and manufacture of these medicines typically relies on automated apheresis devices, significantly reducing the time it takes to perform a cell collection and easing the burden on both patients and donors, while maintaining quality.
Blood is now part of complex supply chains that support both development of therapeutics and their commercial deployment, with components often genetically modified to confer disease-modifying attributes. In addition, for a growing list of indications, automated apheresis technology – the same platforms used to collect material for modification – is being deployed to help patients manage their symptoms as they wait for curative therapies to become available.
Racing for the Cures
The progress in CGTs is often measured in continued regulatory successes, which reflect a growing list of intractable illnesses that have recently become tractable. These include late-stage blood cancers, treated with autologous chimeric antigen receptor (CAR)-T cell therapies made from patients’ own mononucleated or T cells collected via apheresis. Some patients who had failed every other treatment experienced a curative turnabout following CAR-T treatment.
The most recent CGT buzz surrounds two new therapies for sickle cell disease (SCD), bluebird bio’s Lyfgenia and Vertex/CRISPR Therapeutics’ Casgevy (also approved for β-thalassemia). The former will be bluebird’s third marketed gene therapy, while the latter became the first FDA-approved, CRISPR-based gene-editing therapy. And both therapies – as well as bluebird’s Skysona to treat cerebral adrenoleukodystrophy and Zynteglo for β-thalassemia – are made by modifying CD34+ hematopoietic stem cells that have been derived from patients’ own blood via apheresis.
In fact, apheresis is used to collect CD34+ cells for at least five approved therapies and two in late-stage clinical trials (see table).
As a result, optimising apheresis protocols has become a crucial part of clinical development for cell-based therapies. Much like the other stages of CGT manufacturing, standardisation is the goal in order to reduce time required, complexity, and cost. Developers therefore rely increasingly on automated apheresis platforms, given their speed, consistency and ability to generate data that can be used iteratively to improve the process.
In a recent example of such efforts, a team led by John Manis, M.D. from Boston Children’s Hospital and Harvard Medical School shared data last year demonstrating how data gleaned from an automated apheresis system could be leveraged to improve collection. Dr. Manis’ team performed a retrospective analysis of collection procedures for patients with SCD, performed on automated Spectra Optia systems.
Sickled red blood cells can change blood viscosity, leading to unique challenges like clumping that can make it more difficult to separate blood components. This can make it harder to collect the high yields of patient CD34+ cells needed to make an autologous gene therapy dose, sometimes extending the collection process over several days. But the team analysed apheresis data to identify opportunities for optimisation. By implementing new methods from these suggestions, the group saw CD34+ collection efficiency increase from 4.9% to 36.8% – more cells in less time.
In addition, apheresis is now the most common method of CD34+ collection for hematopoietic stem cell transplantation, less invasive than bone marrow harvest and generating higher yields. Over 20,000 such transplants are performed each year in the U.S. for a variety of cancers and immune-related diseases. This includes both autologous procedures (where a patient’s own cells are apheresed and then later used to help reconstitute their immune system) and allogeneic transplants from a matched donor.
Becoming the Treatment
Beyond fuelling the development and production of cells for advanced therapies, apheresis itself is also used as a therapy. Therapeutic apheresis procedures can remove or exchange specific cell types, antibodies, red blood cells and other harmful components. As is the case for patients with SCD, this includes replacing sickled cells with those from healthy matched donor cells. Often, apheresis is done in conjunction with an infusion of donated material, such as therapeutic plasma exchange (TPE) or automated red blood cell exchange (RBCX).
Groups such as the American Society of Hematology (ASH) recommend RBCX over simple transfusion in certain circumstances. Patients with SCD, for example, may regularly be treated with transfusions that can improve an excruciating pain episode. However, too many infusions may cause a dangerous condition called iron overload. By contrast, in automated RBCX, the sickled red blood cells are rapidly removed and replaced with health donor cells. The procedure can also be optimised in order to utilise the ideal amount of blood for each patient.
Therapeutic apheresis is also used for hundreds of other indications through management of blood components, everything from neurological conditions to cardiac diseases. It has typically been performed in large medical centres, limiting its utility to those located nearby or others willing to travel for treatment of an acute crisis. However, recent regulatory changes and government investments are expected to make the procedure more broadly available, and offered closer to home. By improving access, it may be possible to leverage apheresis in some instances as a maintenance therapy, reducing the patient burden and systemic costs connected to acute care.