Page 1760 - Hematology_ Basic Principles and Practice ( PDFDrive )

1564 Part IX Cell-Based Therapies

failure is predominantly immune mediated, where recipient T cells controls; all eight patients engrafted with a low rate of acute GVHD.
play a dominant role in rejecting donor hematopoietic cells. The A similar study utilized haploidentical MSCs in pediatric patients
risk of graft failure therefore increases with the degree of human with hematologic malignancies and hemophagocytic lymphohis-
leukocyte antigen mismatch, the intensity of pretransplant condition- tiocytosis. Compared with a historical control group, there were
ing, and ex vivo graft T-cell depletion. The majority of preclinical comparable rates of engraftment, although patients receiving MSCs
murine studies examining the use of human MSCs have utilized had significantly less grade III–IV acute GVHD. Interestingly, no
immune-defective nonobese diabetic (NOD)/severe combined patients in either of these studies developed chronic GVHD. Finally,
immunodeficiency (SCID) mice that have received sublethal doses a study of adult patients with high-risk hematologic malignancies
of radiation prior to human HSC transplantation. MSCs isolated found comparable rates of CB engraftment in patients receiving
from human fetal lung, fetal BM, adult BM, and placenta enhance donor-derived (mostly haploidentical) MSCs to that of a concurrent
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engraftment of single human CD34 CB, although results were not control group. All patients receiving MSCs had rapid donor engraft-
statistically significant using placental MSCs. Both placental and BM ment with a low incidence of chronic GVHD and no grade III–IV
MSCs enhance double-CB engraftment in the NOD/SCID mouse acute GVHD.
model. Third-party human BM MSCs also increase the engraftment In addition to being given early in SCT to support HSC engraft-
of double CB compared with single CB. Both human placental and ment, MSCs have been employed to promote ex vivo expansion of
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BM MSCs also significantly decrease single-cord dominance in this HSCs. In an elegant study by de Lima et al, adult patients with
model. In an effort to identify MSC subsets that may show enhanced hematologic malignancies receiving double-CB transplant had the
ability to support HSC engraftment, MSCs expressing markers that smaller CB expanded in ex vivo coculture with third-party MSCs,
enrich for CFU-F activity such as the low-affinity nerve growth then infused on day 0 following receipt of the unmanipulated
factor receptor (LNGFR, CD271) and STRO-1 have been examined. larger CB unit. Patients had significantly more rapid neutrophil
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The infusion of selected human CD271 marrow-derived MSCs has and platelet engraftment and higher cumulative incidence of
been compared with the infusion of standard MSCs for engraftment neutrophil and platelet engraftment when compared to a matched
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of human CD133 peripheral blood cells into NOD/SCID mice. historical control group. The expanded cord predominated early
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In this study, CD271 MSCs displayed full MSC CFU-F activ- post-SCT, while the unmanipulated cord predominated long term.
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ity (with none in the CD271 fraction) and demonstrated one- to The authors attribute this observation to coculture increasing
threefold higher proliferation compared with standard MSCs. While progenitor cells committed to megakaryocyte and myeloid lineages,
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both MSC subsets increased engraftment, CD271 MSCs resulted and depleting cells important in long-term repopulation. Interest-
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in greater CD45 donor cell engraftment. Similarly, both STRO-1 ingly, several other clinical trials in which MSCs were coinfused
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and STRO-1 MSCs have been shown to increase BM, peripheral with allogenic BM also demonstrated that, despite successful donor
blood, and spleen engraftment of human CB cells in this model, HSC engraftment, donor MSCs cannot be recovered from the
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although STRO-1 MSCs are superior in this effect. The MSC donor marrow compartment posttransplant. This observation suggests that
source may also impact the effect of MSCs on engraftment. In murine allogeneic MSCs do not meaningfully engraft into the host BM,
models, syngeneic murine BM-derived MSCs significantly increase but rather likely support the newly engrafted donor HSCs through
donor murine HSC engraftment, whereas donor-derived MSCs the transient expression of hematopoietic cytokines and immune
significantly decrease engraftment, and third-party MSCs have no modulation.
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effect. In contrast, in a NOD/SCID model, autologous or allogeneic
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MSCs comparably increase myeloid engraftment of human CD45
cells. This suggests that, at least in a murine model of SCT, MSCs SAFETY PROFILE OF ADOPTIVELY TRANSFERRED
are not immunologically inert, and that the donor source of MSCs MESENCHYMAL STROMAL CELLS
can lead to profound differences in engraftment depending on the
transplant model. MSCs had no effect in two canine models of SCT Numerous studies on a variety of conditions have thus far docu-
using different MSC and HSC donor sources. Third-party MSCs mented safety following infusion of MSCs, and a recent metaanalysis
(either from primary culture or an immortalized clonal population) of 36 studies (including 11 SCT studies) demonstrated no association
had no impact on the engraftment of canine haploidentical BM with acute infusion toxicity, organ toxicity, malignancy, infection, or
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cells following total-body irradiation when compared with BM cells death, with a significant association only seen with transient fever.
alone, with half of the animals rejecting grafts and half developing The genomic stability of cultured adult stem cells and MSCs in
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fatal acute GVHD. Donor-derived BM MSCs also had no impact on particular is robust and not as significant a source of concern. Based
engraftment in a canine leukocyte antigen-identical transplant model upon the immunosuppressive properties of MSCs, downstream
using nonmyeloablative conditioning (1 Gray), a model in which effects on malignant cells and infections have been of particular
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costimulation (CTLA4) blockade or anti-CD154 has been successful. concern in SCT patients. The study by Ning et al is the only
Failure of MSCs in these canine models may be attributed to numer- published study reporting an increase in relapse rates following MSC
ous reasons, including the source of MSCs, intensity of conditioning, infusion, although the study did not report statistical analyses and
absence of posttransplant immunosuppression, and/or the dosing did not preserve the randomization. The inverse relationship found
schedule of MSCs. Finally, MSCs have been studied in a nonhuman between GVHD and relapse in this study, however, does fit with
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primate model of autologous CD34 intra-BM transplant in which numerous other studies documenting the same effect (likely due to
autologous BM MSCs increased the percentage of donor CFUs found decreased GVL) and warrants continued long-term monitoring in
in recipient BM, although the primates were not followed long term. patients receiving MSCs in the malignant setting. Increased rates of
infectious complications have been reported in several small nonran-
domized trials, but as previously stated no association was found in
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CLINICAL TRIALS OF MESENCHYMAL STROMAL a recent meta-analysis. Cytomegalovirus (CMV) viral loads and the
CELLS TO PROMOTE HEMATOPOIETIC STEM rate of CMV disease were higher than expected in 31 patients receiv-
ing MSCs as treatment for GVHD or hemorrhagic cystitis. All cases
CELL ENGRAFTMENT of CMV disease, however, occurred in a GVHD-affected organ and
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most were described as mild. Furthermore, this study was single arm
A number of clinical trials have been published demonstrating the without even a historical comparison group reported, so it is difficult
use of MSCs to promote allogeneic HSC engraftment. Several clinical to ascribe a causative effect. A cohort of pediatric patients receiving
trials have evaluated the use of MSCs following CB transplantation MSCs as treatment for steroid-refractory GVHD had comparable
using third-party or haploidentical MSCs. Following infusion of rates of CMV, Epstein-Barr virus, and adenovirus when compared to
haploidentical MSCs, pediatric patients with high-risk acute leuke- historical controls, although adenoviral infection resulted in decreased
mia had engraftment and rates of GVHD comparable to historical survival, particularly when it occurred following MSC infusion.