The Future of Cell Therapies: Are You Using the Best Tools for Success

Cell therapies are some of the most advanced modalities in modern medicine, potentially transforming outcomes for previously untreatable diseases. However, cell therapies require cutting-edge approaches to ensure their safety, efficacy, and scalability. Next Generation Sequencing (NGS) is the modern solution best suited to the complexities of developing donor-derived cell therapies, offering many advantages over traditional Polymerase Chain Reaction (PCR).

Key Benefits of NGS over PCR for HHV Detection in Donor-Derived Cell Therapies:

Viral contamination poses a significant risk for all cell-derived biotherapeutics, especially donor-derived cell therapies. Donor screening and monitoring is essential, as it can lead to serious clinical consequences in recipient patients who are often immunocompromised.

Human herpesvirus (HHV) specifically poses nuanced risks in cell therapies. The majority of people in the world carry some form of HHV, with the World Health Organization estimating that about 64.2% have herpes simplex virus type 1 (HSV-1). Consequently, rejecting all affected donors, including those with latent viruses, can severely limit the availability of donor cells.

NGS has several benefits over PCR when it comes to the detection and risk assessment of viruses like HHV in donor-derived cell therapies.

1. Detecting Active Replication

NGS transcriptomics can specifically identify actively replicating viruses. This is crucial when working with donor cells that may have latent HHV which may or may not be replicating as a consequence of cell expansion and patient delivery.

PCR methods, on the other hand, do not differentiate between latent and active forms of HHV, leading to false positives. This makes it harder to assess the actual viral risk of donors - creating unnecessary concerns and hindering product phase progression.

2. Regulatory Alignment

The International Council for Harmonization (ICH) has been evolving its guideline, Q5A(R2), to favor NGS over PCR for viral safety testing of cell-based biotechnology products. It acknowledges the broader detection capabilities and advantages of NGS over traditional methods like PCR-based nucleic acid amplification tests (NATs) in viral safety evaluations of donor-derived therapies and notes that targeted or non-targeted NGS can be used to replace the large number of PCR assays for virus-specific detection. It states, "targeted or non-targeted NGS can be used to replace the large number of PCR assays for virus-specific detection." ¹

3. Increased Resource Efficiency

PCR may seem like a lower-cost option upfront, but it becomes apparent how much more resource-intensive it can get when false positives trigger further testing. When PCR detects viral DNA (including latent viruses), additional testing/retesting for replication is required, which often leads to costly delays. In contrast, the all-encompassing nature of NGS significantly reduces the need for revalidation as it provides replication-specific results in a single test.

The advantage of NGS is the high sensitivity that can discriminate between live virus and inactivated virus or viral fragments. NGS also requires less sample material than PCR so there is more for patients. Overall, by switching to NGS, you can expedite your cell therapy's development​.

4. Broad Detection Capabilities

NGS offers broad-spectrum viral detection and can identify known and unknown viruses by sequencing the entire viral genome. This makes it a better option for broad viral screening, especially in donor-derived cell therapies where the donor's virome may not be fully known​. PCR, on the other hand, is virus-specific and limited to detecting known sequences.

Cell therapy developers can screen for multiple viruses, including HHV, with just one NGS test, removing the need for several rounds of specific PCR tests for each virus​​.

5. Clinical Progression and Decision-Making

Using NGS streamlines a cell therapy's progression through clinical phases by enabling adequate and efficient viral safety testing. And if latent HHV is detected in the cell material, timely risk assessments can be performed, and risk mitigation strategies put in place.

The Bottom Line

When all the challenges posed by HHV in donor-derived therapies are considered, NGS emerges clearly as a better, cost-effective yet regulatory-compliant solution. It streamlines product development, aligns with ICH, FDA, and EMA recommendations, and eliminates unnecessary costs and delays. Choosing NGS is not just a technical upgrade; it is a move towards better risk management and faster clinical development.

1. ICH Q5A (R2), https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf (accessed 23Nov23)

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