New Approaches to Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Cancers Laurence J. N. Cooper, MD, PhD
Corresponding author Laurence J. N. Cooper, MD, PhD Department of Pediatrics, Unit 907, Children’s Cancer Hospital, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail:
[email protected] Current Oncology Reports 2009, 11:423–430 Current Medicine Group LLC ISSN 1523-3790 Copyright © 2009 by Current Medicine Group LLC
About 30 years have passed since the fi rst children underwent allogeneic hematopoietic stem cell transplantation (HSCT). Since then, there have been major improvements to identifying and expanding pools of donors, mobilizing and harvesting hematopoietic stem cells, conditioning therapies, transfusion medicine, antimicrobials, immunosuppression, and supportive care. These advances have broadened the application of HSCT to treat malignant and nonmalignant pediatric disorders. Currently, most children and young adults with cancer who undergo allogeneic HSCT are identified as having a malignancy that would be lethal if not for the biologic therapy that HSCT imparts, and remarkably, many of these patients can be cured. However, this cure still comes with costs, including infections, graft-versus-host disease, loss of potential, and psychosocial and fi nancial stresses. New approaches are increasingly available that focus on immune modulation to reduce the burdens of HSCT while improving its therapeutic benefit.
Introduction Pediatric allogeneic hematopoietic stem cell transplantation (HSCT) is the infusion of donor-derived hematopoietic stem cells (HSC) into a child, adolescent, or young adult after myeloablative or immunosuppressive conditioning regimens with intent to restore hematopoiesis and provide a graft-versus-tumor (GVT) effect. The conditioning treatments employ a combination of chemotherapies and sometimes radiation therapy to provide an antitumor effect, as well as the immunosuppression
needed for the successful engraftment of allogeneic HSC. The engrafted HSC provide the recipient with donorderived lymphocytes and a new immune repertoire that can specifically recognize remaining tumor cells. The science of transplant biology helps us understand that the premise of allogeneic HSCT is based on obtaining an immune response against remaining recipient tumor cells and that the future of HSCT is shaped by the promise of immunotherapy.
Eligibility Transplant centers and third-party payers maintain lists of pediatric malignant conditions that are treatable with allogeneic HSCT (Table 1). In addition, there are conditions typically associated with cytopenias and/or lymphopenias—including, but not limited to, myelodysplastic syndrome, severe aplastic anemia, Fanconi anemia, Wiskott–Aldrich syndrome, Chediak–Higashi syndrome, immunodeficiencies such as with hyper immunoglobulin M, and X-linked lymphoproliferative disease—that can be treated with allogeneic HSCT to restore hematopoiesis and prevent the emergence of associated malignancies. The exact malignant diagnosis and accompanying disease burden susceptible to an allogeneic GVT effect changes over time. For example, as the risk of nonrelapse mortality has diminished, allogeneic HSCT can be considered as an initial therapeutic modality for a risk-stratified approach to treating relapsed or refractory Hodgkin lymphoma [1]. In contrast, the availability of new kinase inhibitors may persuade some programs to delay allogeneic HSCT, especially using an unrelated donor, for patients with Philadelphia-positive acute lymphoblastic leukemia (ALL), who rapidly obtain a durable and complete remission, compared with the practice in the era before imatinib of proceeding directly to allogeneic HSCT in CR1 [2]. The decision to undertake, and timing of, allogeneic HSCT is typically made in a group setting with input from multiple attending physicians, nurses, and allied health personnel factoring the patient’s comorbid conditions, kinetics of response and relapse of malignant disease, predictors of early relapse, availability of a suitable donor, accessibility of family caregivers, and fi nancial approval. As most
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Table 1. Typical pediatric malignant indications for allogeneic HSCT Special malignant features
Initial presentation
1st CR
2nd CR
≥ 3rd CR
Relapse/ refractory
–
No
No
Consider
Yes
No
t(9;22) or induction failure
No
Consider
Yes
Yes
No
T-ALL
–
No
No
Consider
Yes
No
AML
–
No
Consider
Yes
Yes
Yes
Malignancies B-ALL B-ALL, high risk
Biphenotypic acute leukemia
–
No
Consider
Yes
Yes
Consider
Secondary leukemia
–
No
Yes
Yes
Yes
Consider
CML
–
No
Consider
Yes
Yes
Yes
JMML Lymphoma Hemophagocytic lymphohistiocytosis Solid tumors
–
Yes
Yes
Yes
NA
Consider
Non-Hodgkin and Hodgkin
No
No
Consider
Yes
Yes
Familial and/or severe
Yes
Yes
NA
NA
Consider
High risk: neuroblastoma, renal cell carcinoma, Ewing’s sarcoma
No
No
Consider
Consider
Consider
AML—acute myelogenous leukemia; B-ALL—B-cell acute lymphoblastic leukemia; CML—chronic myelogenous leukemia; CR—complete remission; HSCT—hematopoietic stem cell transplantation; JMML—juvenile myelomonocytic leukemia; T-ALL—T-cell acute lymphoblastic leukemia.
patients now receive intensive upfront therapy before consideration for allogeneic HSCT, they often present with comorbid conditions, but increasingly these are not barriers to transplantation. For example, patients can successfully undergo allogeneic HSCT who have markedly impaired renal function. Furthermore, advancements in supportive care, such as improvements in antifungal agents, have generated decision algorithms based on the expectation that children with diminishing burden of invasive fungal infections can be safely managed during and after allogeneic HSCT.
Quality of Life Patients who present for allogeneic HSCT on the modern pediatric service can be children, adolescents, and young adults. As a cohort, they have typically received multiple rounds of cytotoxic agents that impact their sense of well-being and long-term potential. Given the associated morbidity of allogeneic HSCT, pediatric oncologists and associated allied health personnel can actively intervene in the peri-transplant period to improve quality of life (QOL) and include discussions of physical, mental, social, sexual, and emotional health during the consenting process [3]. At least in adults, major predictors of decreased QOL are acute and chronic graft-versus-host disease (GVHD), impaired pre-transplant functioning, lower educational level, short interval after HSCT, female gender, reduced social support, interpersonal confl ict, and sexual dysfunction. Interventions can and should be undertaken to improve QOL; for example, an organized in-patient
exercise regimen is usually well-tolerated and can improve sense of well-being.
Choice of Allograft HSC can be obtained from peripheral blood, (neonatal) umbilical cord blood (UCB), and bone marrow from related and unrelated donors using a variety of mobilization schema. Currently, there is general consensus that for patients undergoing their fi rst allogeneic HSCT for an underlying malignancy, an HLA-matched sibling or possibly a one-antigen HLA-mismatched parent or child are the donors of fi rst choice. If a related donor is unavailable, an unrelated non-neonatal donor and UCB donor(s) may be selected. Unrelated nonmanipulated bone marrow and peripheral blood must be HLA-matched, whereas UCB can be mismatched at up to two alleles. Related donors can be mismatched at up to three alleles (haploidentical) if the allograft is effi ciently depleted of T cells. It remains an area of research whether unrelated UCB donors offer superior outcomes compared with haploidentical donors. However, as each source of HSC obtained for treatment of a particular malignancy has benefits and limitations, pediatric oncologists typically choose bone marrow, peripheral blood, or UCB based on institutional experience and priorities, patient characteristics, donor preferences, and countrywide standard practices. An area of debate is whether unrelated allogeneic donors will emerge as the primary choice for an allograft as HLA class I and II typing becomes more refi ned, the pool of donors expands, and
New Approaches to Allogeneic HSCT
early toxic deaths are avoided [4]. The biologic basis for shifting to the preferred use of unrelated donors is based on the ability of their allogeneic T cells to recognize a broader array of tumor-derived immunogenic minor histocompatibility antigens (mHAgs) compared with HLA-identical family donors, which may lead to an improved GVT effect. Of course, GVHD may occur between a donor and recipient if there are unappreciated differences in major histocompatibility antigens or mHAgs are presented by normal tissue(s).
Manipulation of the Allograft HSC from healthy donors can be directly obtained from bone marrow or UCB and can be enriched in peripheral blood and bone marrow by the supraphysiologic dosing of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor (and perhaps in the future by blockade of CXC chemokine receptor type 4). The donor-derived bone marrow, peripheral blood stem cells, or UCB product can be modified ex vivo before infusion or in vivo after infusion to improve engraftment and limit expected complications. For example, to augment engraftment when there are limiting numbers of HSC (eg, when adult-sized patients undergo allogeneic UCB transplantation [UCBT]), two UCB units can be combined for a patient infusion or HSC. CD34+ or CD133+ cells can be numerically expanded ex vivo from one or multiple UCB units using growth factors [5,6] sometimes including the copper chelator tetraethylenepentamine [7], Notch ligand [8], or mesenchymal stromal cells (MSC) [9]. The allograft can also be manipulated to remove unwanted cells, such as excess HLA-mismatched T cells. Currently, this is typically accomplished using antibody-conjugated paramagnetic beads and positively selecting (enriching) CD34+ HSC and discarding nonmagnetic cells, including T cells. New technology using clinical-grade fluorescence-activated cell sorting operating in compliance with current good manufacturing practice (cGMP) is becoming available in specialized facilities for enriching HSC that have aldehyde dehydrogenase activity. Approaches are also available to T cell deplete the infused allograft in the peri-transplant period. For example, antithymocyte globulin and alemtuzumab have been used before and after infusion of HSC (and cyclophosphamide has been given after HSC infusion) to reduce allogeneic T-cell function and numbers.
Typing of the Allograft In the 40 years since crossmatching was described to type the highly polymorphic HLA molecules for kidney transplantation, investigators have refi ned the ability to identify the HLA class I molecules present at varying densities on nearly all healthy nucleated cells and the HLA class II molecules expressed on hemopoietic cells and other cells after
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injury or inflammation. Matching donor and recipient is initially based on the HLA class I genes HLA-A, HLA-B, and HLA-C, and HLA class II genes DRB1, DQB1, and DPB1. Currently, at most major centers, high resolution typing includes direct sequencing of the HLA alleles. The frequency and severity of acute GVHD is dependent on the degree of mismatch between HLA molecules, which is curtailed when non-neonatal donors and recipients are matched for eight alleles (at HLA-A, HLA-B, HLA-C, and DRB1). However, as mentioned, HLA mismatches can be tolerated for UCB-derived allografts. HLA expression can also be used to predict a therapeutic immune response between donor and recipient. Enhanced natural killer (NK)-cell alloreactivity can occur when there is a mismatch between inhibitory receptors for self–HLA class I molecules on donor NK cells and the HLA class I ligands on recipient tumor cells. NK cells are activated for lysis when “self” HLA class I alleles are absent on the allogeneic targets (“missing self”). With the appreciation that engrafted NK cells can mediate an immune response against acute myelogenous leukemia (AML), matching of potential donor and recipient pairs has expanded beyond HLA typing to include the immunogenetics and phenotype of the killer immunoglobulin-like receptor (KIR) repertoire [10]. Outside of the setting of haploidentical HSCT for patients with AML and possibly for children with T-lineage and B-lineage ALLs [11], there is no clear consensus that KIR-ligand incompatibility predicts an improved GVT effect based on identification of alloreactive NK-cell subsets, which is presumably due to multiple confounding variables associated with T-replete allogeneic HSCT, including UCBT.
Choice of Conditioning Regimen Combinations of chemotherapies, radiation therapies, and immunotherapies have been used to provide the recipient with an antitumor effect and immunosuppression necessary to prevent graft rejection. Reduced-intensity conditioning regimens are typically selected to reduce anticipated post-transplant complications and when comorbid conditions are present that preclude ablative therapies. To help safeguard patients from end-organ damage when undergoing ablative regimens, doses of chemotherapy, such as busulfan, are targeted based on real-time assessment of pharmacokinetics. In addition to the application of new chemotherapy-based conditioning regimens, novel approaches to standard total body irradiation are being undertaken that attempt to reduce toxicity, such as by using image-guided helical tomotherapy that can specifically target bone marrow and lymphoid compartments [12].
Second Allogeneic HSCT A second allogeneic HSCT is undertaken in response to graft failure and may be considered as salvage therapy
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for malignant relapse after HSCT. Hematopoiesis can be restored with a second allogeneic HSCT, often using reduced intensity reconditioning regimens. In the absence of an HLA-matched related donor, haploidentical HSCT and UCBT have been successfully used to treat primary graft failure. In cases of relapse of underlying malignancy or emergence of certain second cancers after allogeneic HSCT, pediatric oncologists have undertaken second allogeneic HSCT, including UCBT. Advances in supportive care (eg, care of children requiring mechanical ventilation), prevention/management of sinusoidal obstruction syndrome, the ready availability of additional HSC donors, and the use of alternative/reduced-intensity conditioning regimens have greatly improved the outcome of children after second allogeneic HSCT [13]. Given that the 1-year survival for some children undergoing second HSCT is 56%, this therapeutic option should be presented to patients and parents particularly when there is a reduced burden of malignant disease at the time of transplantation [14].
Graft-Versus-Host Disease Despite advances in DNA-based tissue typing and selection of HLA-compatible donors, a major complication of allogeneic HSCT is GVHD, which is an immunologic disorder commonly affecting the liver, gastrointestinal tract, skin, and sometimes other organs such as the lung. GVHD occurs when infused and/or engrafted T cells recognize disparate HLA molecules (major histocompatibility antigens) or mHAgs on normal cells. To prevent clinically significant GVHD, pediatric oncologists have delivered combinations of at least two immunosuppressive medications, typically a calcineurin inhibitor given with methotrexate, mycophenolate mofetil (MMF), or systemic glucocorticosteroid after infusion of the allograft. Recognizing that there is a narrow therapeutic index, patients are maintained at targeted levels of calcineurin inhibitors based on real-time measurements of steady-state levels. New combinations of immunosuppressive medications, such as using sirolimus, may blunt GVHD without loss of GVT-effect and a phase 3 trial comparing a sirolimus-based prophylaxis regimen is underway (COG ASCT0431). Early detection may provide improved opportunities for intervention and, possibly, prevention of acute GVHD. For example, increased plasma levels of soluble interleukin (IL)-2Rα, IL-8, hepatocyte growth factor, and tumor necrosis factor (TNF) receptor 1 appear to be predictors of GVHD and early-phase clinical trials are evaluating a role for blocking TNF-α using etanercept. Extracorporeal photopheresis (ECP) as an approach to immune modulation (through induction of lymphocyte apoptosis, increasing the immunosuppressive cytokine IL-10, modulating dendritic cells, and escalating the number of regulatory T cells) is being studied as a treatment for steroid-refractory GVHD [15]. New approaches to reducing the
morbidity and mortality of GVHD are typically predicated upon the notion that the pathogenesis of acute GVHD involves 1) tissue damage from conditioning regimen; 2) donor T-cell activation; and 3) infl ammation [16]. Therefore, clinical strategies are being implemented during conditioning to reduce host tissue damage and in this context immunomodulatory agents (eg, statins [17], MMF [18], denileukin diftitox, and anti–IL-2Rα) and anti-CD20 monoclonal antibodies are being evaluated. In addition, infusions of immunomodulatory cells, such as MSC and regulatory T cells are being used in clinical trials. Chronic GVHD can be worrisome for the approximately 30% of children who develop this complication after allogeneic HSCT [19]. Some approaches to treating acute GVHD are being applied to upfront treatment of chronic GVHD, such as using MMF [20]. However, second-line treatment options for chronic GVHD remain limited, and include employing cytotoxic antibodies (antithymocyte globulin, alemtuzumab), cytokine-blocking agents (etanercept, daclizumab), immunomodulating modalities (ECP), and antimetabolites (pentostatin) [21]. New insights may become available as single nucleotide polymorphisms are used to predict for chronic GVHD and improved classification systems are implemented for stratification of patients to clinical trials [22].
Infusion of Donor-derived T cells Engraftment after allogeneic HSCT leads to the outgrowth of donor-derived lymphocytes and offers one of the best examples of the exquisite ability of T cells to target tumor cells. T cells can also be directly infused after infusion of HSC to specifically target underlying malignancies and opportunist infections (Fig 1.). One or more donor lymphocyte infusions (DLI) have been used to restore immunity after T cell–depleted HSCT, complete donor chimerism, and provide an antitumor effect. The DLI immediately provides the recipient with a polyclonal population of T cells that has broad repertoire with the expectation that some of the administered T cells will recognize mHAgs expressed by recipient tumor cells, but not by normal recipient cells, nor by donor-derived hematopoietic cells. This premise has been fulfilled for a subset of immunogenic tumors, such as chronic myelogenous leukemia and one or more DLIs are undertaken if leukemic relapse is detected. The well-recognized problem of DLI occurs when the infused T cells inadvertently target HSC, leading to allograft rejection, or attack normal tissues, leading to GVHD. To limit these toxicities, investigators have infused T cells that have undergone anergy induction to alloantigens and genetically modified the donor-derived lymphocytes to express the thymidine kinase (TK) gene from the herpes simplex virus that renders the TK+ T cells sensitive to conditional ablation in vivo using ganciclovir in the event of clinically significant toxicity [23]. Phase 1 and 2 trials have been undertaken with TK+ DLI infused early after haploidentical HSCT to successfully restore
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Figure 1. Allogeneic hematopoietic stem cell (HSC) transplantation provides a platform for immunotherapy infusing T cells and natural killer (NK) cells. The donorderived HSC may be manipulated before infusion to enhance kinetics of engraftment and reduce morbidity. To enable engraftment of HSC and treat residual malignancy, the recipient receives a conditioning regiment, shown here with an emphasis on immunosuppression. Donor (pink box)–derived lymphocytes (dashed box) can be infused into the recipient (solid gray box) as prophylaxis or treatment. For example, NK cells can be infused before day 0 to augment immunity and improve engraftment. T cells can be generated that have effector and regulatory functions for prevention and treatment of disease. T cells can be identified with endogenous specificity for malignancies and pathogens. T cells can also be rendered specific for tumor antigens using gene therapy. GVHD—graft-versushost disease.
T-cell immunity in these severely lymphopenic recipients [24••]. Another approach to limiting the toxicity of T-cell infusions is to generate donor-derived T cells with desired specificity ex vivo before adoptive transfer. This has been successfully accomplished for mHAgs [25], as well as antigens from one or more opportunistic pathogens [26••], such as cytomegalovirus (CMV) [27], EpsteinBarr virus (EBV) [28], adenovirus [29], and aspergillus [30]. The infusion of clinical-grade antigen-specific T cells for prophylaxis and treatment of viruses and malignancies has made fundamental advances in our understanding of T-cell therapy and design of adoptive immunotherapy trials. It is now appreciated that there is a need for concomitant antigen-specific help provided by CD4+ T cells [31]; small numbers (105 cultured cells/kg) of minimally manipulated T cells can be effective in the setting of immunodominant antigen exposure (viremia) [32]; infused T cells can be long-lived [33]; lymphodepletion improves persistence of infused T cells using mechanisms of homeostatic expansion; transfer of central memory T cells leads to improved persistence [34]; and exogenous administration of cytokines, such as IL-2 [35] and IL-7 [36], may improve T-cell survival and diversity of repertoire. It has generally been assumed that the donor must be immune to the pathogen to raise T cells against viral antigens, but the recent observations that viral-specific T cells can be generated from UCB and naïve individuals challenges this assertion [37,38]. It may be possible for ex vivo culturing technologies to generate antigen-specific T cells from functionally naïve populations, leading to the expectation that experimental conditions may be established to reproducibly break tolerance to tumor-associated antigens (TAA). Some tumors, such as B-lineage ALL, are difficult
to generate an immune response to due to the immune tolerance to TAA and lack of costimulatory molecules on the blasts that are used by T cells to provide a fully competent immune response. Investigators have therefore used genetic engineering to render T cells specific for TAA by introducing αβ T cell receptor chains, such as specific for mHAg, which are HLA-restricted, or single-chain chimeric antigen receptors (CARs), which directly recognize cell-surface molecules, such as B-lineage–specific antigens on tumor cells (as well as normal B cells), independent of HLA [39,40•]. Both approaches are in clinical trials; for example, patients with melanoma received autologous T cells expressing introduced TCR transgenes specific for melanoma antigens [41] and patients with lymphoma and chronic lymphocytic leukemia received autologous T cells genetically modified to express CD20-specific or CD19-specific CARs [40•,42,43]. Recognizing that generating and releasing clinical-grade patient-specific products takes time, investigators are developing approaches using off-the-shelf reagents, such as artificial antigen-presenting cells (aAPCs), to rapidly and reproducibly generate HLA-restricted antigen-specific T cells and CAR+ T cells [44]. Off-the-shelf antiviral therapy is becoming available based on the data that partially HLA-matched EBV-specific T cells have been infused after allogeneic HSCT with clinical response, despite the possibility for a curtailed therapeutic effect due to immune-mediated clearance if the recipient recognized the nonshared HLA antigens [45,46]. A multicenter clinical trial (NCT00711035) to establish the efficacy of infusions after allogeneic HSCT of “most closely HLA matched” pre-banked CMV, EBV, and adenoviral-specific T cells is accruing patients, with intent to fi le for orphan drug status. Somewhat unexpected is
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the welcomed observation regarding the apparent lack of GVHD from these infusions to date. This is surprising because, generally, there is a high precursor frequency (1%–10%) of primary (unmanipulated) T cells with inherent ability to directly recognize allogeneic MHC molecules that would cause GVHD. Presumably present in the banks are a subset of these same potentially alloreactive T cells that crossreact with viral peptides. An alternative approach to off-the-shelf T-cell therapy is demonstrated by the infusion of murine T-cell tumor-specific precursors that can be infused across HLA barriers [47]. One approach to avoiding the need for adoptive immunotherapy is to genetically modify HSC themselves to express desired T-cell immunoreceptors, thereby engineering the allograft for improved GVT effect upon HSC engraftment and emergence of genetically modified lymphocytes with redirected specificity.
Infusion of Natural Killer Cells NK cells have been infused to augment immune response against AML. For example, Miller et al. [48] infused haplo-identical NK cells after lympho-depleting chemotherapy and demonstrated a therapeutic response in patients with AML. This has been used as a basis to infuse haploidentical NK cells as part of the conditioning therapy before HLA-identical–related donor HSCT (NCT00402558) and in patients with solid tumors, such as neuroblastoma (NCT00698009). Recognizing that NK cells can participate in antibody-dependent cell-mediated cytotoxicity, investigators have combined NK cell infusions with therapeutic mAb, such as rituximab, after HSCT (NCT00383994) and epratuzumab (NCT00941928). The NK cells prepared for these trials are typically obtained after steady-state apheresis and large-scale depletion (using CliniMACS device) of CD3+ T cells using antibody-conjugated to paramagnetic beads followed by activation with IL-2. Competing technology is emerging using aAPC, MSC, and EBV–transformed lymphoblastoid cells, to directly ex vivo propagate NK cells obtained from peripheral blood and UCB to clinically sufficient numbers. To enhance the therapeutic potential of NK cells, genetic engineering has been used to introduce a CAR [49]. Because engraftment of donor-derived NK cells are not generally associated with GVHD, NK cells may emerge as an attractive platform for cellular therapy after allogeneic HSCT.
Conclusions Allogeneic HSCT for pediatric neoplasms can be used to treat categories of patients who have poor prognostic factors. This powerful technology increasingly provides a spectrum of children, adolescents, and young adults with a therapeutic platform that can be tailored by the pediatric oncologist to reduce toxicities and improve efficacy. The future of allogeneic HSCT undoubtably lies with the ability to manipulate the immune response to improve the therapeutic effect against the underlying malignancy without exacerbating GVHD. Adoptive immunotherapy after HSCT—perhaps one day instead of allogeneic HSCT—allows investigators to reduce the intensity of HSCT therapies, which lowers costs, widens eligibility, and improves outcomes. Already, clinical successes have been achieved when tumor-specific T cells are infused without the need for infusion of HSC. Institutions that invest in developing facilities that can generate biologics in compliance with cGMP will be at the forefront of developing and implementing these new cellular therapies. To broaden the application of new treatments for pediatric allogeneic HSCT in general and immunotherapies in particular, pediatric oncologists urgently need a federal and institutional regulatory environment and a collaborative mechanism that will facilitate physician-scientists to undertake multicenter cell-therapy trials powered for efficacy. The success of these trials will benefit patients in fi rst-world countries and can be adopted by investigators in developing countries who care for about 80% of the world’s children with cancer.
Acknowledgment Dr. Susan Kelly is acknowledged for her kind review of this manuscript.
Disclosure No potential confl ict of interest relevant to this article was reported.
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Infusion of Mesenchymal Stromal Cells Clinical-grade MSCs can be isolated and numerically expanded from human tissues. These cells have a potent ability to modulate immune responses and clinical studies have been based on their immune-modulatory properties and ability to support hematopoiesis. For example, MSC have been infused to treat steroidresistant GVHD [50].
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