How can diagnostic laboratories accelerate the clinical adoption of allogeneic cell therapies?
This interview is based on a recent overview article published by members from the College of American Pathologists Personalized Healthcare Committee and the Histocompatibility and Identity Testing Committee, who conducted a scoping literature review to better understand the most significant challenges of ACT for laboratory medicine and pathology.
Dr Matthew Anderson and Dr Fabienne Lucas (both members of the College of American Pathologists’ Allogeneic Cell Therapy Project Team) explore the role of surrogate biomarkers in assessing the persistence and efficacy of allogeneic cell therapies (ACTs), highlighting the challenges in developing reliable, standardized biomarkers. They also provide their insights on emerging technologies and the importance of cross-disciplinary collaboration to overcome current limitations and improve the clinical application of ACTs.
Matthew Anderson
Allogeneic Cell Therapy Project Team
College of American Pathologists (IL, USA)
Dr Anderson serves as Chief Medical Officer and Executive Vice President of the Versiti Medical Sciences Institute (WI, USA), which focuses on translational research and providing clinical services in transfusion medicine, hematology care and diagnostics. Dr Anderson is also the Medical Director for the Versiti Diagnostic Laboratories (WI, USA), a national provider of specialty diagnostics for blood diseases. Dr Anderson received his undergraduate degree from UC San Diego (CA, USA) and completed an MD/PhD program at the Medical College of Wisconsin. He went on to complete residency training in anatomic pathology and hematopathology at Stanford University (CA, USA), followed by fellowships in molecular pathology and histocompatibility. Prior to joining Versiti, Dr Anderson served as an Assistant Professor and Assistant Director of the Stanford Histocompatibility, Immunogenetics, and Disease Profiling Laboratory.
Fabienne Lucas
Personalized Health Care Committee | Allogeneic Cell Therapy Project Team
College of American Pathologists (IL, USA)
Fabienne Lucas, MD, PhD, FCAP, is an Assistant Professor in Hematopathology at the Department of Laboratory Medicine and Pathology at the University of Washington, Seattle (WA, USA). With a rich background in hemato-oncology, immunology and flow cytometry, she currently serves the International Clinical Cytometry Society (ICCS) community as DI Committee Chair and Councilor, and the CAP (IL, USA) Personalized Health Care Committee (PHC) as a member and co-lead of the allogeneic cell therapy project with Dr Anderson.
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- What role do surrogate biomarkers play in assessing ACT persistence and efficacy, and how reliable are they currently?
- What are the biggest challenges in developing reliable and standardized biomarkers for ACTs?
- How could these be overcome?
- In the absence of standardized biomarkers, how do you ensure reproducibility and interpretability of response markers in ACT trials?
- What novel monitoring approaches (e.g., liquid biopsies, digital pathology, high-dimensional flow cytometry) are showing promise in enhancing ACT safety?
- Do you have any advice on aligning bioanalytical strategies with emerging regulatory guidance around cell and gene therapy products?
- What is the biggest unmet need in ACT-related bioanalysis that, if solved, could dramatically accelerate clinical translation?
What role do surrogate biomarkers play in assessing ACT persistence and efficacy, and how reliable are they currently?
The persistence of allogeneic cells can be measured by flow cytometry, molecular assays to detect specific genetic modifications introduced into the allogeneic cells, and molecular approaches to detect multiple genomes in a sample (e.g., chimerism testing). To our knowledge there are no published data that formally evaluate these techniques in a standardized way to determine how reliable they may be for allogeneic cell detection more generally.
What are the biggest challenges in developing reliable and standardized biomarkers for ACTs?
Most ACTs are in the preclinical and phase I/II stages of development, which likely explains why our literature search revealed a relative paucity of published information regarding which biomarkers are the most important or useful for a particular type or class of ACT. Compounding this issue is the diversity of allogeneic cell therapies under development including cell of origin and mechanism of action. For example, the biomarkers that are relevant for an allogeneic immune effector cell may be quite different than for a mesenchymal stem cell.
How could these be overcome?
Collaboration between biomarker laboratories and the companies developing cell therapies is critical to ensure that the right biomarker strategies are being developed and adopted as ACTs move through clinical trials. It is also important for clinical diagnostic laboratories and in vitro diagnostics (IVD) manufacturers to participate to ensure that clinical diagnostic assays are available once ACTs enter routine clinical practice.
In the absence of standardized biomarkers, how do you ensure reproducibility and interpretability of response markers in ACT trials?
In our experience, some biomarkers utilized for ACT clinical trials leverage existing CAP/CLIA certified clinical diagnostic assays that are used routinely for patient care. For example, some ACTs require HLA compatibility between the recipient and the cell product for the mechanism of action. The ACT product and potential recipients are typically HLA genotyped using standard clinical diagnostic assays utilized for hematopoietic and solid-organ transplantation. However, we are also aware of the need to modify standard clinical diagnostic assays for use in ACT clinical trials. For example, standard chimerism assays to measure donor cell engraftment post-hematopoietic cell transplant can typically distinguish between 2–4 genomes in a sample. Some ACT products are derived from multiple donors (either as sequential doses or as a pooled product), which can result in greater than 2–4 genomes being present in a sample. This then necessitates modifications to standard clinical assays to distinguish the pooled donor ACT product from the recipient.
What novel monitoring approaches (e.g., liquid biopsies, digital pathology, high-dimensional flow cytometry) are showing promise in enhancing ACT safety?
Emerging monitoring technologies are currently employed or in development in research settings or in the setting of autologous cellular therapies and hold significant promise for integration into clinical diagnostics. Such technologies include liquid biopsy, high-definition single cell assays [1], absolute quantification of ACT numbers by droplet digital PCR (ddPCR), spectral and multiparametric flow cytometry, and various digital pathology approaches, incorporating morphology-based data and AI-driven image analysis.
These strategies ensure appropriate dosing, facilitate real-time monitoring of ACT expansion, kinetics, persistence and potential relapse, offering insights into safety, efficacy and early detection of adverse events. They also offer spatial resolution and high-dimensional immunophenotyping of ACT and interactions within the tumor microenvironment. However, their integration into routine clinical practice will depend on further validation and standardization to ensure reliability and reproducibility across diverse patient populations.
Do you have any advice on aligning bioanalytical strategies with emerging regulatory guidance around cell and gene therapy products?
Again, collaboration is key. As ACT developers receive feedback from regulatory agencies on biomarker strategies for their clinical trials (inclusion/exclusion criteria, monitoring, etc.), it is important that this information is shared (to the extent possible) with the laboratories that are performing testing or developing biomarkers in support of the trial. Decisions made at an early stage of biomarker development (e.g., choice of analytical platform, assay design, etc.) can greatly impact the ease of translating biomarkers into assays that can be widely deployed in clinical laboratories.
What is the biggest unmet need in ACT-related bioanalysis that, if solved, could dramatically accelerate clinical translation?
There will likely not be one single biomarker or testing modality that is universally applicable for all ACTs. Our intent in researching and writing our article was to increase awareness in the pathology community about the emergence of ACTs and encourage laboratory professionals to work across traditional laboratory specialties (molecular, histocompatibility, flow cytometry, histology and many others) to create the multi-modality biomarker approaches that will likely be needed as ACTs progress towards the clinic.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Bioanalysis Zone or Taylor & Francis Group.
