Overcoming Manufacturing Challenges to Unlock Cell Therapy’s Potential

With over 2,000 cell therapies in development, the field of medicine is on the brink of a seismic shift as these treatments will soon be used as first-line therapies for a variety of debilitating diseases.¹ Unlike conventional drugs and interventions that often manage symptoms, cell therapies aim to address the root causes of diseases at the cellular level, underscoring their potential to provide targeted, effective treatments with the possibility of long-lasting remission or even cures.

Regenerative medicine, focused on repairing damaged organs or tissues, is one of the areas where cell therapies are making strides. For example, by harnessing stem cells' ability to differentiate into a variety of cells, it is possible to repair heart tissue after a heart attack and to regenerate neurons for treatment of neurodegenerative diseases. Genetically modified cell therapies are also being used to treat certain hereditary diseases, such as the adenosine deaminase severe combined immunodeficiency (ADA-SCID), which severely compromises the patient’s immune system. This treatment involves collection of hematopoietic stem cells from a patient’s bone marrow, genetically modifying the cells using a viral vector, and infusing edited cells back to the patient. These cells then can produce functional adenosine amidohydrolase (ADA) enzyme that is required for proper immune system functioning.

Perhaps the most widely known application of cell therapies is in the treatment of certain blood cancers utilizing chimeric antigen receptor T cells (CAR-T). This involves reprogramming a patient's T cells to recognize and attack cancer cells by latching onto antigens on the cancer cells’ surface. This approach has shown remarkable success in treating B-cell malignancies, leading to remissions in terminal pediatric and adult patients. While highly effective for treatment of blood cancers, CAR-T therapy’s effectiveness against solid tumors has been limited. To that extent, another type of immunotherapy, T cell receptor-engineered T cells (TCR-T), holds promise. Recently, the first TCR-T therapy (Tecelra), was approved by the FDA for treatment of metastatic synovial sarcoma. By targeting a wider array of antigens, TCR-T cell therapies can recognize cancer cells that might evade CAR-T cells due to antigen loss or variation.

Leveraging technology to streamline manufacturing

The path from lab to clinical application for these innovative treatments is still fraught with complexities and manufacturing challenges that stand in the way of unlocking their full potential. Manufacturing cell therapies differs fundamentally from other biologics. It involves intricate steps such as cell selection, activation, genetic modification, cell expansion, and formulation, all under strict aseptic conditions. The additive effects of genetic and physiological differences of starting material (patient’s or donor’s cells), variability in quality of input materials, and differences in processing conditions, make it difficult to standardize processing, effective scaleup, and maintain consistent quality from batch to batch.

Scalability is another major challenge. Producing individualized therapies on a large scale requires handling high-throughput processing without compromising quality, efficacy, and safety. Decentralized manufacturing models, such as point-of-care manufacturing, are being explored to bring production closer to the patient, reducing vein-to-vein time. However, site-to-site variability in expertise and capabilities makes this strategy difficult to implement. For example, if a site has limited ability to perform analytical in-process and release testing, any logistical advantages of decentralization can quickly be erased with added time and cost of sending samples to an external lab.²

Emerging innovations address these challenges. Automated manufacturing systems and Process Analytical Technology (PAT) are being integrated to reduce reliance on manual interventions during manufacturing and improve process robustness. For example, Cellares, which is developing an end-to-end automated cell therapy manufacturing platform (Cell Shuttle), has integrated a Raman spectroscopy-based continuous process monitoring solution. This tool monitors multiple critical process parameters (CPPs) in real-time during the cell expansion and enables feedback process control to maintain optimal conditions. In another example, Terumo Blood and Cell Technologies, the manufacturer of the Quantum Flex Cell Expansion System, is also integrating an on-line process monitoring solution with their Quantum Flex platform. This process monitoring solution provides operators with up to 720 data points per day of key cellular metabolic parameters—glucose and lactate—which are used to estimate cell density, predict cell expansion trajectory, and optimize media perfusion rate. The synergy between PAT and automation enables a more dynamic approach to process management, reduces manual interventions and lowers contamination risk.

Future directions in personalized medicine

Personalized medicine is the frontier where treatments are tailored to each patient, and cell therapies are at the heart of this development. In the near future, genetic profiling and biomarkers will likely have a significant impact on the field by helping streamline cell selection, select optimal therapy targets, and identify patients that are more likely to respond to treatment. Multi-omics technologies, for example, may help detect viral or microbial contaminations faster for drug release testing while single-cell genomics, transcriptomics, and proteomics may help characterize cell populations and evaluate therapeutic effects at a single-cell level.

CRISPR-Cas9 is another technology revolutionizing the field of allogeneic cell therapies, where donors’ cells, rather than patient’s own cells, are used as starting material. One of the main challenges for allogenic therapies is the risk of immune rejection, necessitating donor-recipient matching, which increases complexity and limits scalability. This is where the highly targeted and precise gene-editing capabilities of CRISPR-Cas9 are utilized to reduce the immunogenicity of donor cells by knocking out specific genes. Additionally, with CRISPR, genes can be corrected or inserted with a high precision and at a lower cost compared to viral vector-based editing, potentially leading to enhanced efficacy, less complexity, and lower manufacturing cost.

Cell therapies are poised to revolutionize the treatment of a wide array of diseases by offering solutions that are both targeted and personalized. Accelerating the path from lab to patient, reducing cost, and increasing availability involves not only technological advancements and innovative logistical strategies, but also collaborative efforts between industry stakeholders, regulatory bodies, and healthcare providers. As we stand on the brink of a new era in medicine, the refinement of cell therapy manufacturing processes is not just a technical necessity but a crucial step toward realizing a future where personalized and curative medicine is the norm. Companies contributing to advancements in this field, such as Cellares, Terumo Blood, Cell Technologies, and many others, play a vital role in shaping this future. By continuing to crack the code of complex manufacturing, we move closer to a healthcare landscape where effective, long-lasting treatments are affordable and available to all who need them.

References

1. American Society of Gene & Cell Therapy (ASGCT), Citeline. Gene, Cell, & RNA Therapy Landscape Report, Q2 2024 Quarterly Data Report.; 2024.

2. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Forum on Regenerative Medicine; Beachy SH, Alper J, Drewry M, eds. Emerging Technologies and Innovation in Manufacturing Regenerative Medicine Therapies: Proceedings of a Workshop—in Brief. Washington, DC: National Academies Press; 2024.