Cell and Gene Therapy Answers: The critical role of biomarkers and analytical testing in adoptive cell therapies
26 January 2024
Adoptive cell therapies have shown great promise in treating certain cancers. As more and more adoptive cell therapies move toward regulatory approval, robust analytical testing and biomarker identification will be key to delivering the full potential of these life-changing treatments. We spoke with Akanksha Gupta, PhD, executive director for cell and gene therapy at Labcorp, to learn more about the latest advancements and remaining considerations in this rapidly evolving field.
What can you tell us about the current landscape for biomarker and analytical testing in the development of adoptive cell therapies?
The landscape for biomarkers and analytical testing for adoptive cell therapies is rapidly evolving. Typically, the clinical trial testing strategy involves the assessment and monitoring of the kinetics to the treatment dose, the level of the target cell population, as well as other indicators of treatment efficacy and safety. In the context of adoptive cell therapies, the functional as well as the phenotypic characterization can provide insights into the potential effectiveness of the product.
As these therapies entail the use of a living drug, assessing the immunological fitness as well as the status of immune activation and differentiation, the memory response as well as the survival capacity—not only during manufacturing but also the final product and post-administration with the patient—is critical.
One of the key assessments analyzed in clinical trials for these therapies is the evaluation of the kinetics of effector cells including the expansion and persistence of these cells post-administration. Since this assessment is bespoke to the product, the development and validation of the assay is required prior to the initiation of a Phase I trial.
Other pharmacodynamic assessments include efficacy biomarkers such as minimal residual disease (MRD) for oncology, as well as understanding the impact on immune system activation post- administration. From a safety perspective, the early detection of adverse effects such as cytokine release syndrome (CRS) and neurotoxicity using biomarkers can lead to timely intervention as well as improvement of safety profiles for the products. Since these therapies can also be immunogenic and induce host immune response, the evaluation of immunogenicity, both humoral as well as cellular, is critical. In addition, the potential generation of the replication-competent retrovirus or lentivirus is also important to analyze in these clinical trials from a safety perspective.
Predictive biomarkers can be leveraged for patient refinement strategies that can enhance the therapeutic outcome. Utilizing assays like next-generation sequencing (NGS), single-cell RNA sequencing and NanoString can generate gene signatures that can be correlated with clinical outcomes, thus allowing for gene expression-based patient enrichment opportunities. Evaluating the antigen of interest using flow cytometry or an IHC approach can also be leveraged for these analyses. As with any biomarker-driven development, the integration of a companion diagnostic strategy can also play a pivotal role in matching the right therapy to the right patient.
Compared to other therapeutic modalities, what are the challenges and unique attributes to biomarker and analytical testing for adoptive cell therapies?
Biomarker testing in adoptive cell therapies, such as CAR Ts, is uniquely complex compared to conventional therapies, such as small molecules and biologics. Unlike traditional therapeutic modalities, these cell therapies are living drugs that can interact dynamically within the patient. There’s a complexity that is attributed to the tumor, the CAR T-cell product and the host immunological milieu; hence, it is important to not only evaluate the host tumor microenvironment but also the CAR T-cell characteristics. Aspects of these are evaluated, not only in the chemistry, manufacturing and controls (CMC) phase, but also post-administration into the patient. Because these therapeutic products are so unique, it is important that the clinical development strategy incorporates timelines for the development of assays pertaining to the analysis of cellular kinetics specifically: qPCR-based vector copy number assay and persistence via a flow cytometry approach.
Additionally, given the patient-specific nature of many cell therapies, the biomarker profiles may be inherently individualized, necessitating a patient-centric monitoring strategy. Given these complexities, it may prove challenging to develop sensitive, specific and reliable assays for monitoring safety and efficacy. The use of multiple biomarkers and complex data analysis can bring challenges in standardizing testing methodologies to compare data across studies.
In addition, some therapies may also target hard-to-reach tissues or tumors, meaning sample collection for biomarker testing can be invasive and intricate. Another consideration is that multiple biopsies from a patient-management perspective can be very burdensome for the patient. This is where the utilization and development of non-invasive methods for testing, such as liquid biopsy, becomes important.
Another unique and challenging aspect associated with these therapies is the potential for long-term persistence of the therapy that underscores the need for long-term monitoring in the event of a second primary malignancy. This needs to be monitored, even post-commercialization of the product. Recently, the U.S. Food and Drug Administration published a safety advisory on the risk of T-cell malignancies among individuals receiving CAR T therapies. The agency believes “the overall benefits of these products continue to outweigh their potential risks for their approved uses,” but requires lifetime follow-up for patients receiving approved CAR T-cell therapies to assess risk of second primary malignancy. It is due to the novel nature of adoptive cell therapies that strategies for the analysis of samples in a diagnostic environment, post-commercialization and approval of the product, are critical.
Another consideration that adds complexity to the analytical and biomarker strategy is the type of product, for instance, autologous versus allogeneic CAR T. With allogeneic therapies, when using donor cells instead of a patient’s own cells, the resident cells may appear foreign to the T-cell receptors of the allogeneic CAR T-cell. This could induce their activation and result in acute graft versus host disease, which needs to be monitored. In addition, high-resolution HLA typing is needed to understand the influence of differing degrees of HLA mismatch between the recipients and donor cell populations.
What impact will advancements in biomarkers have in the future for clinical development of adoptive cell therapies?
Advancements in biomarkers as well as assay platforms and technologies can have profound implications in the development of adoptive cell therapies, ultimately making them more personalized, effective and potentially safer. Advances in NGS and single-cell RNA sequencing can identify unique tumor-specific markers, patient-specific biomarkers or genetic variations that can be instrumental in optimizing patient selection and the CAR T-cell design to ensure that treatments are more precisely targeted.
As we begin to better understand the biomarkers used to identify the mechanism behind treatment resistance and relapse using multi-omic technologies, these therapeutics can be modified to overcome these barriers, improving long-term outcomes. In addition, as more of these therapies get approved, there is the potential to see persistent CAR Ts present from prior treatment that could be confounding.
We can also anticipate the simultaneous development of cell therapy and an associated companion diagnostic (CDx) as a strategy for patient refinement. While a CDx for cell therapies hasn’t been approved at this stage, it is imminent. This convergence of therapeutic development and diagnostics (i.e., integration of biomarker advancement, utilization of multi-omic approaches, digital pathology, incorporation of artificial intelligence and machine-learning algorithms and analysis of these huge datasets) will play a critical role in the development of these transformative therapies.
Lastly, from the therapeutic area perspective, while we have seen adoptive cell therapies developed to target oncology indications—including both hematological and solid tumors—we're also beginning to see them address more prevalent disorders and other therapeutic indications, such as autoimmune diseases.