Hematopoietic Cell Transplantation

Allogeneic HCT refers to the transfer of hematopoietic stem cells from one individual to another with the intent to obtain lifelong engraftment of the administered cells. The use of allogeneic HCT as a cellular immune therapy for acute leukemia first became feasible in the early 1960s after the identification and typing of major histocompatibility complexes (human leukocyte antigen [HLA] system). In the 1970s Thomas and colleagues cured several patients with end-stage leukemia by using HLA-identical siblings after ablating the recipient marrow with total-body irradiation combined with cyclophosphamide. It was evident that the occurrence of graft-versus-host disease (GVHD) reduced the incidence of leukemic relapse, suggesting that donor lymphocytes can eradicate tumor cells that survive preparative regimens.

Hematopoietic Cell Transplantation

Allogeneic HCT refers to the transfer of hematopoietic stem cells from one individual to another with the intent to obtain lifelong engraftment of the administered cells. The use of allogeneic HCT as a cellular immune therapy for acute leukemia first became feasible in the early 1960s after the identification and typing of major histocompatibility complexes (human leukocyte antigen [HLA] system). In the 1970s Thomas and colleagues cured several patients with end-stage leukemia by using HLA-identical siblings after ablating the recipient marrow with total-body irradiation combined with cyclophosphamide. It was evident that the occurrence of graft-versus-host disease (GVHD) reduced the incidence of leukemic relapse, suggesting that donor lymphocytes can eradicate tumor cells that survive preparative regimens.

Donor Source

Various allogeneic graft sources have the potential to produce a potent antineoplastic GVL/T effect to sustain complete remission of malignant disease. Donor sources for HCT in children include cells from bone marrow (BM), umbilical cord blood (UCB), or mobilized peripheral blood (PBSC) from related or unrelated donors. In addition to the type of the allogeneic graft, secondary non-HLA selection factors such as age of the donor, sex of the donor, total cell count, cytomegalovirus status, and ABO blood groups may contribute to the selection of a donor. However, the most important selection criterion for a donor source is HLA matching. At present, the role of high-resolution matching at HLA-A, HLA-B, and HLA-DRB1 is clearly established. However, the significance of the other loci, including HLA-C, HLA-DQ, HLA-DRB3 and DRB5, and HLA-DPB1, is less clear and is currently under investigation.

HLA-identical sibling donors are considered the preferred stem cell source for allogeneic HCT; they have less transplantation-related mortality, acute GVHD (aGVHD), and chronic GVHD (cGVHD), along with better disease-free and overall survival (OS) than the unrelated donors. Past studies have shown that use of a PBSC source produces a more rapid hematopoietic reconstitution; however, they are associated with a significant increase in cGVHD. Not only is cGVHD significantly higher for patients receiving PBSC in comparison with BM (33% vs 19%, respectively; P <.001) but in the pediatric population treatment-related mortality, treatment failure, and overall mortality are also higher in the PBSC group. The use of antithymocyte globulin (ATG) in the preparative regimen lowers the incidence of cGVHD. A distinct advantage of unrelated donor UCB or haploidentical related donors is their rapid availability, and transplantation with cord blood requires less stringent HLA matching than transplant with bone marrow or peripheral stem cells. In general, mismatched cord blood cells are less likely than BM to cause both aGVHD and cGVHD, without losing the GVL effect. Hematologic and immunologic reconstitution is slower in UCB transplants than in BM recipients, which is associated with an increase in infection-related morbidity. A limiting factor of UCB transplants is the cell dose. Blood from the umbilical cord and placenta is rich in hematopoietic stem cells but is often limited in volume. Data from pediatric studies reveal a lower survival in patients who receive a cell dose of less than 3 × 10 ⁷ /kg when compared with patients who received greater than 3 × 10 ⁷ cells/kg. This limitation can be partially overcome by using double UCB over single cord. Thus current practice supports the use of UCB donors, which provide a cell dose of greater than 3 × 10 ⁷ cells/kg. Because of the limitation in cell number presented by UCB, newer ex vivo expansion approaches are being used to target molecular pathways involved in stem cell self-renewal, such as the Notch signaling system. The use of T-cell depleted haploidentical donors (usually parents) is another option that has been explored to overcome the limitation of obtaining matched unrelated donors or UCB. However, the overall rate of chronic GVHD was significantly higher in patients who underwent haploidentical transplants while the relapse-free survival and disease-free survival (DFS) rates did not differ significantly between the groups. Alloreactive natural killer (NK) cells, which express combinations of activation and inhibitory killer-cell immunoglobulin-like receptors, seem to be the primary mechanism for the GVL effect.

Preparative Chemotherapy Regimen

Several factors contribute to the outcome of HCT. In particular, the preparative chemotherapy regimens play a key part. The goal of preparative or conditioning regimens in patients undergoing HCT for malignant diseases includes providing significant immune ablation to prevent graft rejection and reduce the tumor burden. Traditionally myeloablative conditioning (MAC) regimens were thought to be the only means of achieving these goals. However, in recent years the reduced-intensity conditioning (RIC) regimens have been shown to be effective in HCT. Selecting the intensity of the conditioning regimen depends on the disease type, remission status, age of the patient, donor availability, and comorbid conditions. Myeloablative regimens often consist of alkylating agents with or without total-body irradiation (TBI) and are expected to ablate marrow hematopoiesis, preventing autologous hematologic recovery. High-dose TBI has been widely used as part of myeloablative regimens, especially in patients with acute lymphoblastic leukemia (ALL). Data from a large retrospective study and a randomized controlled trial in pediatric ALL patients with TBI as part of the preparative regimen demonstrated better event-free survival (EFS) outcomes when compared with myeloablative preparative regimens containing high-dose chemotherapy alone. Although TBI reduces the risk of relapse, TBI-based regimens have significant late effects in children, and is often associated with an increased risk of gastrointestinal, hepatic, and pulmonary toxicities, cataracts, endocrinopathies, second malignancies, impaired growth and development, and cognitive delay.

In recent years, use of a RIC for allogeneic HCT has demonstrated efficacy with an acceptable rate of donor engraftment and lower transplant-related morbidity and mortality relative to MAC regimens. Results of a phase 2 trial of RIC transplantation in children ineligible for MAC conditioning found that favorable outcomes could be achieved using a RIC regimen of busulfan, fludarabine, and antithymocyte globulin. A retrospective comparison of RIC and MAC regimens in pediatric patients with acute myeloid leukemia (AML) showed that relapse rates were similar for both RIC and MAC regimens, and interestingly the transplant-related mortality (TRM) was also similar for both regimen groups. These data indicate that long-term DFS can be achieved using reduced-intensity conditioning regimens, and may be considered in patients who are ineligible for MAC regimens.

The addition of antibodies targeting T cells, such as ATG and alemtuzumab (Campath 1H), to conditioning regimens is a commonly used approach to decrease the incidence of graft rejection and prevent GVHD. Several studies have shown that the administration of horse or rabbit ATG results in a significant reduction in the risk of aGVHD grades III and IV. Alemtuzumab has been shown to be effective in decreasing the incidence of GVHD without increasing the risk of relapse and, with a significant delay in immune reconstitution, there was no increase in infectious complications or relapse in recipients of alemtuzumab.

Recipient Characteristics

In children with a malignancy, sometimes the underlying nonmalignant disorder requires consideration when planning conditioning regimens. For example, patients with inherited DNA repair disorders such as Fanconi anemia are very sensitive to conventional conditioning protocols because of high chromosome fragility, and MAC regimens involving alkylating agents and ionizing radiation have been associated with a high incidence of transplantation-related toxicity and mortality. RIC regimens are often used in patients with nonmalignant disorders and have been shown to be associated with a low TRM; however, these patients have been shown to have a significantly higher incidence of primary graft failure.

Acute Lymphoblastic Leukemia

Relapsed ALL is the most common malignant childhood disease for which an HCT is offered, particularly in those who experience marrow relapse on treatment or within 18 months of stopping therapy. The role of HCT in treating isolated central nervous system (CNS) disease is uncertain, with most opting to use intensive chemotherapy and delayed CNS radiation as the first option. Another group in which HCT is being explored is that with a high risk of relapse. A prospective study in 7 countries investigated the outcome of patients with very high-risk ALL in first complete remission (CR1) found that the 5-year DFS was 40.6% in children allocated to chemotherapy alone, compared with 56.7% in those assigned to HCT ( P = .2). The Children’s Cancer Study group (CCG-1921) investigated the role of HCT from HLA-matched family donors in ALL patients with ultrahigh-risk features, and reported the 5-year EFS for all patients to be 58.6%; patients without cytogenetic abnormalities had a 5-year EFS of 77.8%.

Acute Myeloid Leukemia

The use of HCT for patients with AML has evolved significantly in the last 3 decades. In the 1980s a common practice in North America was to offer matched family donor stem cell transplantation in CR1, whereas the European groups favored a more conservative approach with HCT in second complete remission (CR2). In the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) studies, the outcome was better for those allocated to matched related HCT in CR1, and the OS and DFS was superior for allogeneic HCT in comparison with chemotherapy alone or autologous purged HCT. In the POG study, there was no advantage for autologous bone marrow transplantation (BMT) in CR1 over chemotherapy alone. A more recent analysis of combined CCG and POG AML studies, however, demonstrated that the superior survival advantage of allogeneic BMT for AML in CR1 may be limited to the intermediate-risk group of patients, with no significant benefit over chemotherapy for low-risk and high-risk patients. At present, AML-CR1 allogeneic BMT is not recommended to low-risk patients (those with RUNX1-ETO, inv16, t[16;16], and NPM1 mutations; Down syndrome AML; acute promyelocytic leukemia). By contrast, allogeneic BMT remains the only curative treatment option after relapse regardless of the initial risk factors.

Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a relatively rare hematopoietic malignancy in the pediatric and adolescent population. In CML, allogeneic HCT offers a long-term DFS in patients in chronic phase and is the only proven curative approach. In the European Group for Blood and Marrow Transplantation (EBMT) study the OS ranged from 60% to 80%, with better results in matched sibling donors (87%) than in matched unrelated donors (59%). Over recent years, the increased use of tyrosine kinase inhibitors (TKIs), such as imatinib, and clinical efficacy in CML have been well established, resulting in only a minority of pediatric patients undergoing upfront HCT. Achieving a major cytogenetic remission by prior imatinib treatment at the time of HCT has been found to predict a 5-year OS of 81% to 89% in unrelated matched HCT in adults. The exact role of HCT for children and adolescents with CML is controversial, with studies to establish its role being considered in the International BFM Study Group and the Children’s Oncology Group (COG).

Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoiesis with variable BM dysplasia and cellularity, progressive cytopenias, and susceptibility for transformation to AML. Current World Health Organization criteria classify MDS into the following subdivisions: refractory cytopenia (RC), refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T). MDS in children has a poor prognosis and, despite attempts to use various treatment modalities, currently the curative treatment choice is allogeneic HCT. Smith and colleagues reviewed 37 pediatric MDS cases at a single institution and revealed factors associated with improved 3-years DFS, including not having received pre-HCT chemotherapy and a shorter interval (<140 days) from time of diagnosis to transplant. The 3-year DFS in patients who did not receive pre-HCT chemotherapy and those who had a shorter interval to transplant was 80%. Therefore, children with MDS should be referred for allogeneic HCT soon after diagnosis, and pre-HCT chemotherapy does not appear to improve outcome.

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is an uncommon disease occurring exclusively in young children that includes among its symptoms fevers, infections, massive hepatosplenomegaly, pulmonary infiltrates, and rash. Intensive chemotherapy is mostly unsuccessful in JMML because of an increased risk of treatment-related death. The European Working Group on Childhood Myelodysplastic Syndromes and Bone Marrow Transplant Working Group (EWOG-MDS/EBMT) reported the largest cohort to date (N = 100) in which the 5-year EFS was 52%, and used a myeloablative preparative regimen with high doses of busulfan/cyclophosphamide/melphalan (BU-CY-MEL). The OS was 64%, without significant differences in the EFS between matched related or matched unrelated donors. Both acute and chronic GVHD are associated with a lower risk of relapse. At present the COG is conducting a randomized phase II study comparing a busulfan/fludarabine (BU-FLU) conditioning regimen with a BU-CY-MEL conditioning regimen, hypothesizing less TRM and comparable EFS with the BU-FLU regimen.

Lymphoma

The OS of children and adolescents with newly diagnosed Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) disease approaches 90%, with the use of combination chemotherapy with either autologous or allogeneic HCT considered for refractory patients. Unfortunately, greater than 60% of patients with Hodgkin lymphoma who undergo autologous HCT fail to achieve complete remission. Evidence suggests that allogeneic HCT have been associated with a significantly lower incidence of relapse of Hodgkin lymphoma compared with autologous HCT, but with no impact on OS and a high incidence of TRM. Gross and colleagues examined the role of allogeneic and autologous HCT in children with refractory or recurrent Burkitt, lymphoblastic, diffuse large B-cell (DLBCL), and anaplastic large cell lymphomas. The 5-year EFS was similar after allogeneic and autologous HCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, it was higher for lymphoblastic lymphoma after allogeneic HCT (40% vs 4%; P <.01).

Limitations to Hematopoietic Cell Transplantation

For most patients undergoing allogeneic HCT the major causes of morbidity and mortality are related to disease relapse, aGVHD and cGVHD, infection, regimen-related toxicity, and graft failure. Other serious acute adverse effects include idiopathic pneumonia syndrome (IPS), engraftment syndrome, and sinusoidal obstruction syndrome (SOS). IPS is defined as the presence of widespread alveolar injury in the absence of active lower respiratory tract infection that occurs following allogeneic HCT. The lung injury generally occurs within 4 months of transplant and is associated with a high mortality rate exceeding 60%. Immunologic cell-mediated injury and inflammatory cytokines contributes to the lung injury. Prompt treatment with corticosteroids and etanercept may reduce the injury.

Engraftment syndrome occurs usually before neutrophil recovery, especially after UCB HCT, and is characterized by fever, rash, weight gain, pulmonary edema, liver and renal dysfunction, and/or encephalopathy. Engraftment syndrome is due to a cytokine storm with capillary leak and is associated with interstitial pneumonitis. Engraftment syndrome has a higher progression to aGVHD and has a lower OS at 2 years (38% vs 54%, P <.001). Prompt treatment of engraftment syndrome with corticosteroid therapy should be initiated on diagnosis.

Another severe complication is the potentially fatal hepatic SOS, previously known as veno-occlusive disease, characterized by the presence of painful hepatomegaly, jaundice, and fluid retention. The mechanism of action involves damaged sinusoidal endothelium that sloughs out and obstructs the hepatic circulation, leading to centrilobular hepatocyte injury. Several risk factors increase the incidence of sinusoidal obstruction syndrome, including chronic liver disease, the presence of the C282Y allele of the HFE hemochromatosis gene, and common variants of the glutathione S -transferase gene that alters the metabolism of busulfan and cyclophosphamide.

Acute Graft-Versus-Host Disease

aGVHD is an immune response stimulated and accentuated by injury resulting from the preparative regimen used before transplantation. A postulated mechanism of aGVHD involves the activation of toll-like receptors on various cells, which then leads to the release of inflammatory cytokines. Activation of toll-like receptors blocks the suppressive effects of regulatory T cells, thus permitting the activated alloreactive cytotoxic T cells to enter the circulation and damage organs such as the gut, liver, and skin, resulting in aGVHD.

The reported incidence of aGVHD in children varies widely from 20% to 80%, depending on the major risk factors of HLA matching and donor type (matched or mismatched, sibling) and stem cell source. The National Institutes of Health (NIH) Consensus Development Project defines classic aGVHD as occurring before 100 days after transplant with the presence of aGVHD symptoms and the absence of cGVHD symptoms. Persistent or late-onset aGVHD is defined as occurring after day 100 with the presence of aGVHD symptoms (such as intestinal aGVHD) and the absence of cGVHD symptoms. This situation is not uncommon after unrelated UCB HCT.

Standard aGVHD prophylaxis regimens usually combine a calcineurin inhibitor (tacrolimus or cyclosporine) with short-course methotrexate. The initial treatment of aGVHD involves optimizing the present GVHD prophylaxis and initiation of corticosteroids. Only 50% to 70% of aGVHD cases will have a complete response to steroid treatment. Steroid-refractory aGVHD has been treated with equivalent success with anti–tumor necrosis factor α antibodies (infliximab, etanercept), mycophenolate mofetil (MMF), mTOR inhibitors (sirolimus), interleukin-2 receptor antibodies (daclizumab), ATG, or extracorporeal photopheresis as second-line treatments.

Chronic Graft-Versus-Host Disease

cGVHD is believed to involve autoimmune and alloimmune dysregulation, leading to disordered immunologic reactivity against autologous (self) and allogeneic (donor) antigens. Based on the NIH Consensus Development Project, classic cGVHD is defined as occurring after day 100 post-HCT with the presence of cGVHD symptoms and the absence of aGVHD symptoms. Overlap syndrome is then defined as occurring 100 days post-HCT with the presence of both aGVHD and cGVHD symptoms. cGVHD can potentially affect any organ of the body, although the skin, eyes, oral cavity, gastrointestinal tract, genitourinary system, liver, and lungs are most commonly affected. Other organ systems such as the kidneys or heart can also be affected, although far less frequently. cGVHD of the skin can present as sclerosis (lichen sclerosus–like or lichen planus–like), hypopigmentation or hyperpigmentation, alopecia, keratosis pilaris, and ichthyosis. Musculoskeletal involvement of cGVHD can result in myositis, fasciitis, muscle weakness, cramping, edema, and pain and joint contracture. Ocular cGVHD affects up to 80% of patients and typically presents with dry or gritty eyes (sicca syndrome), photophobia, keratoconjunctivitis, punctate keratopathy, and blepharitis. Pulmonary cGVHD is classified as either obstructive lung disease or restrictive lung disease, and the incidence of lung toxicity ranges from 30% to 60% in children. Bronchiolitis obliterans (BO) is a serious life-threatening manifestation of cGVHD characterized by an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive obstructive lung disease. Pulmonary function tests should be routinely checked at 3 and 12 months after transplantation and at the onset of cGVHD, to determine whether obstructive lung mechanics are present and whether therapy for BO should be initiated. Initial therapy for BO includes a trial of enhanced systemic immunosuppression, with inhaled corticosteroids and pulmonary rehabilitation. Hyposplenism leading to increased susceptibility to encapsulated organism should be considered, with active cGVHD and penicillin prophylaxis initiated. First-line therapy for cGVHD continues to be corticosteroids. Second-line immunosuppressive agents such as MMF, sirolimus, imatinib, rituximab, and extracorporeal photopheresis may be considered. Imatinib may improve sclerodermatous cGVHD, and rituximab may benefit skin and musculoskeletal cGVHD.

Long-Term Effects Not Associated with Graft-Versus-Host Disease

Advances in allogeneic HCT have led to improved patient survival, and long-term complications have increased in importance. Long-term effects may involve the cardiovascular system, lungs, kidneys, CNS, endocrine system, second malignancies, and the psychosocial implications of survivorship. Factors that increase cardiovascular mortality include high cumulative doses of anthracyclines and exposure to radiation therapy that may have included the heart or mediastinum. The metabolic syndrome (central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), associated with development of type 2 diabetes mellitus and atherosclerotic cardiovascular disease is also increased, and needs to be monitored for at follow-up visits. Both busulfan and TBI preparative regimens can lead to impaired pulmonary function tests, either obstructive or restrictive, not related to cGVHD up to 10 years after transplant, necessitating close follow-up. Renal function should also be monitored long term at all follow-up visits, as chronic renal insufficiency can be caused by radiation-induced renal injury and cGVHD.

There is a high prevalence of endocrine dysfunction in long-term survivors, resulting in disturbances in thyroid function, onset of puberty, fertility, bone health, and growth and development. The long-term use of corticosteroids to treat cGVHD can result in a variety of complications including, but not limited to, aseptic necrosis of the bone and osteoporosis, adrenal suppression, and metabolic syndrome. Craniospinal radiation has been implicated as the primary cause of growth failure after HCT as a result of damage to the hypothalamic-pituitary axis, leading to decreased production of growth hormone. Preparative regimens that include TBI and busulfan can lead to premature ovarian failure in some survivors, resulting in absence of or delayed puberty and amenorrhea. As they enter their reproductive years, many women will fail to ovulate after undergoing transplantation, while men potentially become infertile. In addition, the frequency of secondary cancers such as cancers of the skin, oral mucosa, brain, thyroid, bone, and posttransplant lymphoproliferative disease are increased. Any female patient who has had TBI should have monitoring for breast cancer by MRI, initiated in her early 20s. As the number of long-term pediatric HCT survivors increases, more attention is being focused on neurocognitive and psychosocial outcomes. Studies have shown that there is a small but significant decline in IQ in children transplanted for malignant disorders when compared with control subjects, and especially in children who received TBI or craniospinal radiation and those who developed aGVHD. Socioeconomic status continues to be an important determinant of cognitive and academic function. Recognizing the nature and complexity of long-term side effects in children after HCT, it is necessary to maintain frequent and thorough follow-up evaluations to detect issues that may arise as early as possible. Early diagnosis can lead to early intervention and may improve the manifestations of many late effects.

Graft-Versus-Leukemia/Tumor

Allogeneic HCT represents the most common and effective form of immunotherapy in childhood leukemia. Over the past several decades, clinical studies have revealed that the effectiveness of GVL/T in eradicating malignant disease is linked closely to the activity of immunoreactive cells in the graft, particularly the T cells and NK cells from allogeneic BM, PBSC, or UBC. In haploidentical or multiple HLA antigen–mismatched donors, the donor NK cells carry receptors for peptide–major histocompatibility complex molecules on recipient target and are the primary mediators of GVHD. Donor T cells seem to primarily respond to minor histocompatibility antigens expressed on both hematopoietic and nonhematopoietic cells, causing both GVL/T and GVHD. Comparison of relapse rates seen in patients who develop no GVHD, aGVHD, cGVHD, or both aGVHD and cGVHD continue to reveal that the GVL effect is strongly associated with the development of GVHD. This claim is further supported by the fact that there are increased rates of leukemia relapse after T-cell–depleted and identical twin allogeneic HCT.

The GVL effect is affected by several factors, the primary one being minimal residual disease status before transplant, resulting in a higher risk of relapse after HCT in ALL. In haploidentical HCT, it is clear that alloreactive NK cells that kill recipient cells through the recognition of mismatches in the NK cell killer immunoglobulin-like receptor (KIR) play a large role in GVL. Current trials are under way to evaluate the impact of KIR mismatches in the setting of matched unrelated donor HCT in high-risk AML (COG study). An additional advantage of this approach is that activated NK cells can directly lyse GVHD-inducing T cells and host antigen-presenting cells, potentially controlling GVHD.

Novel Cellular Therapies in the Treatment of Childhood Malignancies

Despite the effectiveness of allogeneic HCT and GVL/T in the treatment of hematopoietic malignancies, the leading cause of treatment failure remains relapse of disease. Attempts to generate and enhance cellular cytotoxic responses in vivo have been made using monoclonal antibodies. Although monoclonal antibodies may be directly cytotoxic, most induce antitumor responses via antibody-dependent effector mechanisms, including complement-mediated lysis and antibody-dependent cellular cytotoxicity (ADCC). Monoclonal antibody therapy has resulted in clinical improvements in several malignancies; however, monoclonal antibody therapy has not been curative in most patients. Recently, application of anti-GD2 antibodies in high-risk neuroblastoma with minimal residual disease resulted in significant improvement of survival, but the disease still progressed in at least 40% of the patients. Several cellular-based therapies to create a GVL effect are currently under investigation, including dendritic cell (DC) immunotherapy, bispecific antibodies, chimeric antibody receptor T cells, NK cells, and adjuvant immune therapies.

Dendritic Cell Immunotherapy

DCs can capture and present tumor antigens to T cells, resulting in the development of tumor-specific cytotoxic T cells that can mediate protective antitumor responses. Since the first published DC vaccine trial, numerous clinical studies have established the feasibility and safety of DC vaccinations; however, clinical and immunologic responses have been infrequent and unpredictable, as in a case of pediatric high-grade gliomas ( Fig. 1 ). Several DC vaccines have been used in pediatric tumors, fibrosarcoma, and malignant brain tumors, some with significant responses. Combining DC vaccines with the demethylating agent decitabine to upregulate TAA expression for a child with advanced neuroblastoma resulted in durable complete remission.

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