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A Call for Standardization in Cell Therapy Studies

Commentary on an article by Iain R. Murray, BMedSci(Hons), MRCS, MFSEM, PhD, et al.: “International Expert Consensus on a Cell Therapy Communication Tool: DOSES”

Rodeo, Scott A. MD

doi: 10.2106/JBJS.19.00189
Commentary and Perspective
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The Hospital for Special Surgery, New York, NY

E-mail address: rodeos@hss.edu

Disclosure: The author indicated that no external funding was received for any aspect of this work. On the Disclosure of Potential Conflicts of Interest form, which is provided with the online version of the article, the author checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/F256).

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Commentary

Recently, there has been an explosion of interest in cell therapy. There is currently tremendous confusion among scientists, clinicians, and certainly among patients as to the basic definition of a stem cell. It has become increasingly clear that stem cells are very heterogeneous in their origins and basic biologic activity. At the most basic level, a stem cell is defined by the ability for self-renewal and multilineage differentiation. The International Society for Cellular Therapy has set forth standard criteria that have been well accepted in the field; however, as we learn more about the underlying cellular and molecular mechanisms of progenitor cells, the complexity is daunting. In addition to the 2 most commonly used sources, bone marrow and adipose tissue, numerous tissues contain small populations of intrinsic progenitor cells. Tissues such as amnion, placenta, and umbilical cord blood are also being investigated as readily available stem-cell sources. Furthermore, gene therapy techniques can transform a mature, differentiated cell into a cell that is tantamount to an embryonic stem cell.

It is axiomatic that these diverse cell types will exhibit different biologic activities at the cellular and molecular level. As such, efforts are underway to develop more detailed and refined methods to characterize and classify stem cells. For example, genomics, proteomics, and metabolomics approaches will be required. A recent meta-analysis of randomized controlled trials of cell therapy for the knee published in The Journal of Bone & Joint Surgery highlighted the substantial inconsistency in nomenclature used to describe cell therapies, with a frequent disconnect between the nomenclature used and the actual cell formulation1.

It is in this context that the paper “International Expert Consensus on a Cell Therapy Communication Tool: DOSES” presents an algorithm to assist investigators in reporting salient characteristics of cell therapy formulations, with the overall purpose to improve standardization and transparency in studies reporting on cell therapy. The algorithm contains 5 major categories that are all critically important factors for consideration. The 5 core items include (1) donor (autologous, allogeneic, or xenogeneic), (2) origin of tissue, (3) separation method, (4) exhibited cell characteristics associated with cell behavior, and (5) site of delivery. Like any classification system, the challenge lies in balancing the desire to record detailed information with the need to limit “responder burden.”

I believe that the “E” category (exhibited cell characteristics) is the most important because that information will ultimately characterize the biologic activity of the cell preparation. It will be interesting to see how investigators interpret and provide information to fulfill this category. There is little guidance provided by the authors regarding the specific type(s) of information that should be reported in the E category. I think it is largely appropriate to not be overly proscriptive, allowing wide leeway for investigators to decide what type of information is reported under the E category. Broad application of the DOSES tool by clinicians, investigators, authors, and manufacturers will naturally lead to refinement and further evolution of this system. However, I do believe that, at the least, the composition, biologic activity, and viability of the cells should be reported in the E category. Further studies will undoubtedly identify more refined molecular, genetic, and functional criteria that will be critical for characterization of cell populations.

The paper by Murray et al. provides 1 more addition to a growing number of acronyms that have been proposed for classification of biologic therapies. Two separate publications in 2012 proposed very similar classification systems for platelet-rich plasma (PRP) based on 3 components: (1) the absolute number of platelets, (2) the manner in which platelet activation occurs, and (3) the presence or absence of white blood cells2,3. DeLong et al. used the acronym “PAW” (meaning platelets, activation status, and white-blood-cell presence) for this system2. In 2016, Magalon et al. proposed the “DEPA” classification (meaning dose of injected platelets, efficiency of platelet capture, purity [i.e., the relative composition of platelets, leukocytes, and red blood cells in the PRP], and activation)4. In a 2017 study published via open access, Lana et al. proposed a more complex system with the acronym “MARSPILL.”5 This system records the following parameters: method, activation, red blood cells, spin, platelets, image guidance, leukocytes, and light activation. More recently, Murray et al. proposed the “MIBO” (minimum information for biologics in orthopaedics) criteria6, which indicated 23 items that should be reported for PRP studies and 25 items for cell therapy studies, including information about the patient, the underlying pathology being treated, the preparation protocol for either PRP or a cell therapy formulation, delivery of the treatment, post-treatment protocol, and outcome assessments. Lastly, Jo et al. refer to the “4 D’s” in a discussion about the variability in PRP studies: drug (type of PRP), delivery (method of application), donor (specifics about the patient), and disease (stage or severity of the condition)7. All of these systems attempt to bring some order and standardization to the complex and evolving field of cell therapy.

Perhaps the elephant in the room is the fundamental question: what does it all mean? We need further information to determine the cell source, processing method, and measure(s) of biologic activity that are optimal for specific tissues and types of pathology. Further work is required to identify the “biologic targets” for different tissues and then to identify the measures of cell characteristics and cell behavior (category E) that will allow matching of a specific cell formulation with the desired target tissue. Ultimately, the DOSES system would allow classification of cell formulations into categories that would facilitate clinical research in this area. I encourage clinicians, industry, and authors of both laboratory and clinical studies to begin the use of the DOSES tool, and possibly other algorithms, when communicating the results of cell therapy investigations. In fact, I believe that journal editors should consider adopting such reporting standards as mandatory for publication of studies in this area.

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References

1. Jones IA, Chen X, Evseenko D, Vangsness CT Jr. Nomenclature inconsistency and selective outcome reporting hinder understanding of stem cell therapy for the knee. J Bone Joint Surg Am. 2019 Jan 16;101(2):186-95.
2. DeLong JM, Russell RP, Mazzocca AD. Platelet-rich plasma: the PAW classification system. Arthroscopy. 2012 Jul;28(7):998-1009.
3. Mishra A, Harmon K, Woodall J, Vieira A. Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol. 2012 Jun;13(7):1185-95.
4. Magalon J, Chateau AL, Bertrand B, Louis ML, Silvestre A, Giraudo L, Veran J, Sabatier F. DEPA classification: a proposal for standardising PRP use and a retrospective application of available devices. BMJ Open Sport Exerc Med. 2016 Feb 4;2(1):e000060.
5. Lana JFSD, Purita J, Paulus C, Huber SC, Rodrigues BL, Rodrigues AA, Santana MH, Madureira JL Jr, Malheiros Luzo ÂC, Belangero WD, Annichino-Bizzacchi JM. Contributions for classification of platelet rich plasma - proposal of a new classification: MARSPILL. Regen Med. 2017 Jul;12(5):565-74. Epub 2017 Jul 31.
6. Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF. Minimum information for studies evaluating biologics in orthopaedics (MIBO): platelet-rich plasma and mesenchymal stem cells. J Bone Joint Surg Am. 2017 May 17;99(10):809-19.
7. Jo CH, Lee SY, Yoon KS, Oh S, Shin S. Allogenic pure platelet-rich plasma therapy for rotator cuff disease: a bench and bed study. Am J Sports Med. 2018 Nov;46(13):3142-54. Epub 2018 Oct 12.

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