Page 1761 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 99 Mesenchymal Stromal Cells 1565

While an effect on adenovirus-specific T cells was found in vitro, no medical center service-based care delivery will likely have a substantial
in vivo effect was found, and the authors note significantly higher impact on deployment of MSC-based technologies. See box titled
rates of HLA-mismatched grafts in the MSC group. A retrospective “Cryobiology and Fitness of Thawed MSC Cellular Pharmaceuticals.”
analysis of 1021 patients transplanted at the Karolinska University
Hospital found MSC infusion to be a significant predictor of post-
transplant lymphoproliferative disease on multivariate analysis, a FUTURE DIRECTIONS
finding that has not been previously reported. As none of these
studies were randomized trials, they serve as further reminders that The number of clinical trials examining the use of MSCs for treat-
long-term monitoring in patients receiving MSCs is necessary, par- ment of acute, steroid-resistant GVHD and other immune ailments
ticularly in future randomized trials. is growing exponentially. Subtle differences in donor source, culture
methods, and expansion levels make head-to-head comparisons of
REGULATORY OVERSIGHT OF MESENCHYMAL STROMAL the different MSC products challenging when interrogating their
utility. The European experience in exploiting random donor MSCs
CELLS DEVELOPMENT AND MARKETING APPROVAL to treat GVHD is wide in its breadth and robustness. Although
solely phase II studies, as an aggregate their cumulative experience
The clinical evidence-based development of HSC transplantation as and the very meaningful differences in MSC cell preparation when
a therapeutic modality has historically been performed as “practice of compared to their industrial counterpart, in particular the use of early
medicine”, akin to organ transplantation and transfusion medicine. passage cells, point toward key remedies that may be buttressed by
In this particular setting, the cellular product is considered minimally mechanistic interrogation. Virtually all human clinical trials carried
manipulated and is therefore recognized as a 361 product by the out to date involve the use of culture-expanded MSCs maintained
US Food and Drug Administration (FDA). In contrast, any cellular in their default setting. Preclinical animal data strongly support the
product that requires some adulteration, nonhomologous use, or notion that the use of augmented MSCs prior to infusion, either by
more-than-minimal manipulation is considered a 351 product and the use of cytokine activation, genetic engineering, or reprogram-
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regulated by the FDA as a drug. In order to evaluate these prod- ming robustly, enhances their pharmaceutical potency. Therein lies
ucts on humans in the United States, the academic investigator or the path for MSC v2.0. In closing, understanding this mechanism
company will need to develop a manufacturing process and controls and how it relates to clinical utility remains the only rational
that meet the requirements of the FDA. The FDA’s requirements for path to the successful development of MSCs to their full clinical
manufacturing investigational cell therapy products include adher- potential.
ence to the following regulations: 21 CFR 210/211 Current Good
Manufacturing Practice (cGMP), 21 CFR 600 and 610 Biological
Products General and Biological Products Standards, and 21 CFR Considerations in Development of MSC-like Cells as a Cellular
Pharmaceutical for GVHD.
1271 Human Cells, Tissues, and Cellular and Tissue-Based Products
(HCT/Ps). These regulations require the establishment of systems for The use of allogeneic mesenchymal stromal cells (MSCs) for the
the design, monitoring, and controls of the manufacturing process treatment of steroid-resistant graft-versus-host disease (GVHD) builds
and facility. For an academic researcher or a startup company, estab- upon encouraging phase II clinical trial data published by European
lishing systems and facilities that are compliant with these regulations academic collaborative groups in the past few years. However, a large
requires a considerable amount of resources and time. Consequently, multicenter phase III clinical trial (NCT00366145) conducted in the
manufacturing stands as a major hurdle to overcome for the clinical USA examining the use of an industrial marrow-derived MSC product
translation of cell therapy technologies—particularly for individuals, (Prochymal) reported in 2009 that it failed to meet its primary clinical
companies, or academic health centers with limited resources. MSC- endpoint of achieving a significant increase of complete response of
steroid-resistant GVHD lasting at least 28 days. This pivotal phase III
like cells that have undergone ex vivo culture expansion fall under study does not support the use of Prochymal in this clinical indication
this regulatory oversight, and an FDA Center for Biologics Evaluation and has not gained FDA marketing approval. The field of MSC cell
and Research (CBER) Investigational New Drug (IND) application therapy is faced with a paradox regarding the clinical utility of MSCs
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is mandatorily required to engage in human clinical trials. Clinical for GVHD, with opposite clinical outcomes when testing industrial and
trials demonstrating an impact on clinical outcomes are required to locally sourced MSCs. MSC cell biology informs us that there may
eventually secure FDA marketing approval and Biologics License well be meaningful distinctions between the functionality of industrial
Application (BLA) for reimbursement and deployment. Herein lies MSCs and those manufactured by academic centers. Most typically,
a substantive distinction in traditional evidence-based clinical science a polyclonal pool of culture-expanded random donor MSCs is manu-
and the pathway to widespread adoption of progress in clinical centers factured, and here lies a major difference: academic centers seldom
manufacture more than 5–10 MSC doses from a single volunteer
and the regulatory requirements imposed upon more-than-minimal donor, whereas up to 10,000 doses are manufactured per donor for
manipulated cell products for the same end. Whereas any accredited Prochymal lots. From a cell biology perspective, genetic reprogram-
clinical center can readily adopt practice of medicine cell therapy ming will inexorably occur when progenitor cells are continuously
technologies without licensing requirements, the same is not true culture expanded to achieve large lots of qualified pharmaceutical.
for adoption of more-than-minimally manipulated (e.g., 351) cell Although MSC cultures are polyclonal at onset, expansion pressure
therapies. This regulation of cells as drugs favors a development leads to clonal impoverishment with time. Culture-expanded human
model driven by industry where mass-produced universal product MSCs have been shown to undergo telomere shortening and other
amenable to batch manufacture and release testing is compatible with alterations of phenotype, which may play a role in modifying their
a sustainable business model consistent with drug cell manufacture regenerative and immunosuppressive properties or triggering an
immune response, limiting their survival and function in vivo. Among
and deployment. In contrast, personalized cell medicine, as exempli- these acquired alterations is the gradual entry into senescence of MSCs
fied by autologous PBSC transplantation, is typically provided as a as they approach replicative exhaustion. Although senescent MSCs
medical service within accredited medical centers. Providing such have a virtually indistinguishable marker phenotype from nonsenescent
services within medical centers with the additional encumbrance MSCs, their functional properties, immune in particular, may be signifi-
of BLA requirement is a challenge for which no clear pathway has cantly altered. Clinical data from the Karolinska Institute suggest that
been defined. Although industrial models based on manufacture of late-passage MSCs are less effective than comparable early-passage
personalized cell therapies have been feasible, the business sustain- MSCs with regard to survival outcomes in GVHD patients. The MSC
ability of such has been a challenge, as exemplified by the bankruptcy manufacture protocols utilized by academic collaborative groups would
of Dendreon Corporation (WA, USA), which obtained the first ever predictably minimize meaningful epigenetic reprogramming of MSCs
when compared to industrialized expansion scale, and therein lies a
FDA marketing approval for an industrial manufactured autologous plausible shortcoming to industrial-scale culture expansion of MSCs
cell-based vaccine pharmaceutical. The added requirements for regu- and their effectiveness in human trials.
latory science and innovative reimbursement models in traditional