Cell and Gene Therapy Answers: Bioanalytical support for cell and gene therapy

2 February 2024

Your source for answers to the complex challenges of cell and gene therapy development.

We recently spoke with Daniel Sikkema, executive director of global immunochemistry at Labcorp drug development, regarding bioanalytical support for cell and gene therapy modalities. He shared some of the current challenges in cell and gene therapy, how the Labcorp Bioanalytical Services group contributes to the development of cell and gene therapy and the path forward as new treatments continue to be developed.

Watch the Full Video of Dan >

What challenges exist as cell and gene therapies rapidly enter the development portfolio?

Hear from Dan >

We are witnessing a rapid evolution in the cell and gene therapy domain as new therapeutics enter the market. These therapies have unique and novel capabilities—they can regenerate biologic systems and prevent, treat or cure diseases with a new level of specificity. At the same time, these advances have led to challenges in five key areas:

1. Regulatory 

New molecular, cellular and immunological assays push the limits of current regulations and guidance, which can lead to frequent interactions with regulatory agencies. Moreover, the facility infrastructure and scientific expertise required to support these highly complex new drug modalities can require additional investments.

2. Bioanalytical

With traditional drug development, patients take a drug, and we measure its disposition over time. In contrast, with gene therapy, we give patients the genetic capability to express a certain protein. The genetic material at issue is translated into a protein product in vivo, which could be soluble (e.g., in the blood) or incorporated into cells (membrane or internally). 

As a result, there are a number of assay methods required to support a molecular medicine multiplies as we assess the molecular vector and any immunogenicity. At the same time, we must also assess the bioavailability of the expressed transgene product. It’s quite possible to end up with five to 10 bioanalytical assay methods to assess the overall product, often requiring use of recent technologies such as flow cytometry and molecular assays, as well as immunologic, cellular or tissue analysis.  

3. Clinical trials and support

Adding to the complexity, gene therapy clinical trials are in their very early stages. Studies are typically rather small and are often conducted in extremely rare disease populations; trials can span a decade or more. Numerous challenges can arise, both from reagent and personnel qualification perspectives, when it comes to keeping five to 10 assays in validated status for long periods of time. These studies are very atypical from a historical perspective, since they involve very infrequent sampling and a small number of patients.

Moreover, study enrollment often requires prescreening of patients to ensure they don’t harbor neutralizing antibodies to the delivery vehicle. Assessing immune responses against these viral constructs plays an important role not only in recruiting patients, but also in assessing whether, or when, to incorporate additional rounds of treatment.

4. Immunogenicity

Immune responses to gene replacement therapy can range widely—from relatively benign antibodies binding to the expressed protein—to complete neutralization of the protein product, to allergic reactions, which can have serious consequences. Risk factors vary by product and approach.

For instance, with hemophilia A, patients are missing a blood clotting factor and have bleeding episodes. At first blush, permanent gene therapy treatment would appear preferable to a lifetime of IV infusions. However, hemophilia A has many phenotypes, ranging from small defects in the endogenous protein to a complete absence of the ability to express any protein. Patients with relatively small defects tend to have lower immunogenicity risk versus those who may see the protein as completely foreign. Confounding this issue, many patients with hemophilia A previously received intravenous factor VIII for many years prior to becoming a candidate for a gene replacement therapy. We need to monitor these patients carefully to determine which patients are the best candidates for these types of complex treatments.

5. Cell therapy

Cell therapy programs are evolving very rapidly, with a variety of distinct approaches, especially in the oncology field. Bioanalytical methods to assess the number of circulating cells typically require flow cytometry. At the same time, guidance for flow cytometry best practices has only recently been introduced and continues to evolve. Data management for these studies will likely require the ability to store very large data files, adding to the complexity. 

How does a traditional bioanalytical group contribute to the development of cell and gene therapies?

Hear from Dan >

We’ve witnessed an evolution when it comes to new drug modalities, ranging from early natural products like antibiotics to today’s chemically synthesized compounds, monoclonal antibodies, mRNA/DNA constructs, cellular delivery (e.g., CAR-T), viral vectors and gene replacement therapies.   

Introduction of new drug modalities comes with new regulatory guidance, and Labcorp routinely participates in major symposia to ensure that we follow the most recent guidance globally. Since our foundational regulatory and quality systems are already in place, we have the unique capability to introduce new scientific methods into a regulated bioanalytical environment. 

New challenges will constantly arise, and we are ready, having already dealt with diseases like COVID-19, Zika and Ebola. Our broad historical perspective on drug development empowers us to keep up with the changing times by providing new and lifesaving treatments.

How is Labcorp Bioanalytical positioning for future modalities?

Hear from Dan >

Since new cell and gene therapy modalities are highly complex, Labcorp has made it an enterprise initiative to invest in facilities, leadership and scientific personnel to support these programs. From a bioanalytical perspective, we are expanding our team with high-level scientists that have advanced skills in method development and method validation. We are also hiring principal investigators, project managers, technical writers and other personnel to provide broad program support. These affirmative steps are creating powerful synergy within the Labcorp organization.

Not only are these increased collaboration opportunities advancing our employees’ learning and skill development, but we are also providing a wider range of diverse expertise to keep pace with an evolving field and help advance the development of our clients’ assets.

Learn how we can support your analytical needs to advance your cell and gene therapies by visiting our website.

Read more like this from our experts in our CGTAnswers blog series on additional topics: ddPCRCMConcology Cell & Gene Therapy, Preclinical Oncology and Rare Disease.