Autologous and Allogeneic Cellular Therapies for High-risk Pediatric Solid Tumors




Since the 1950s, the overall survival of children with cancer has gone from almost zero to approaching 80%. Although there have been notable successes in treating solid tumors such as Wilms tumor, some childhood solid tumors have continued to elude effective therapy. With the use of megatherapy techniques such as tandem transplantation, dose escalation has been pushed to the edge of dose-limiting toxicities, and any further improvements in event-free survival will have to be achieved through novel therapeutic approaches. This article reviews the status of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for many pediatric solid tumor types. Most of the clinical experience in transplant for pediatric solid tumors is in the autologous setting, so some general principles of autologous HSCT are reviewed. The article then examines HSCT for diseases such as Hodgkin disease, Ewing sarcoma, and neuroblastoma, and the future of cell-based therapies by considering some experimental approaches to cell therapies.


Since the 1950s, the overall survival (OS) of children with cancer has gone from almost zero to approaching 80%. Although there have been notable successes in treating solid tumors such as Wilms tumor, some childhood solid tumors, exemplified by diseases like high-risk neuroblastoma and metastatic sarcomas, have continued to elude effective therapy. With the use of megatherapy techniques such as tandem transplantation, dose escalation has been pushed to the edge of dose-limiting toxicities, and any further improvements in event-free survival (EFS) will have to be achieved through novel therapeutic approaches.


This article reviews the status of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for many pediatric solid tumor types. Most of the clinical experience in transplant for pediatric solid tumors is in the autologous setting, so some general principles of autologous HSCT are reviewed, followed by an examination of HSCT for diseases such as Hodgkin disease, Ewing sarcoma, and neuroblastoma. The article then looks to the future of cell-based therapies by considering some experimental approaches to effector cell therapies.


Principles of autologous HSCT


Before the introduction of high-dose chemotherapy (HDC) with autologous stem cell rescue (also called autologous HSCT), marrow tolerance was the limiting factor in the escalation of chemotherapy for the treatment of malignancies. With the ability to safely harvest, store, and reinfuse a patient’s own hematopoietic stem cells, doses of cytotoxic therapies for cancer could safely proceed beyond marrow tolerance, thereby allowing more intense treatment of certain malignancies. Two approaches to the use of HDC with stem cell rescue are (1) myeloablative regimens, meaning that no hematopoietic recovery can occur without the stored HSCs, and (2) submyeloablative HDC regimens in which stem cell rescue is used to speed recovery, decrease toxicity, and decrease the interval between courses of chemotherapy, although it is not absolutely required for engraftment. Although the increased treatment intensity may improve disease-free survival for patients with some malignancies, this must be balanced with the increased treatment-related mortality associated with the higher doses of cytotoxic agents, and the potential late effects of more intense cytotoxic treatments and radiotherapeutic regimens in young children. Criteria that may help define circumstances in which HDC with stem cell rescue would be most beneficial include (1) a tumor with good response to induction chemotherapy, but a poor 3- or 5-year EFS, and (2) an HDC regimen that can use multiple agents active against the disease, especially if the agents differ from those used during induction therapy. Although the use of HDC with stem cell rescue is controversial in most diseases, diseases such as Hodgkin disease and high-risk neuroblastoma (discussed later) meet the design criteria listed earlier and have shown improved outcomes in clinical trials.




Hodgkin disease


Although most pediatric patients with Hodgkin disease achieve excellent long-term survival with standard chemotherapy and low-dose radiation therapy, with EFS and OS of 80% and 90%, respectively, many patients have refractory disease or experience relapse. Poor prognosis in these relapsed patients is associated with chemotherapy-resistant disease, short time to relapse (<1 year), extranodal disease at relapse, and poor performance status in adult patients.


Adult studies comparing conventional salvage therapy with HDC with autologous stem cell rescue show the benefit of the HSCT approach in relapsed disease. Following up on a pilot study in 1991 that suggested HSCT might be a better frontline therapy for high-risk patients, a randomized trial was conducted comparing conventional therapy with HSCT. Using a foundation of 4 cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), patients with high-risk features (high lactate dehydrogenase level, mediastinal mass, >1 extranodal site, anemia, or inguinal disease) were assigned to either 4 more cycles of ABVD or HSCT. There was no difference in EFS or OS, discouraging HSCT as frontline therapy for high-risk patients. Linch and colleagues compared a standard intensified HDC regimen (bis-chloroethyl-nitrosourea [BCNU], etoposide, cytarabine and melphalan [BEAM]) and autologous stem cell rescue with mini-BEAM in a randomized trial for relapsed and refractory adult patients, finding improved EFS and lower relapse rate in the intensified arm but similar OS. A large randomized study of patients aged 16 to 60 years with relapsed Hodgkin disease compared 4 cycles of nonmyeloablative Dexa-BEAM with 2 cycles of Dexa-BEAM plus a high-dose BEAM with HSCT. EFS was 55% at 3 years for the HSCT group and only 34% for conventional therapy ( P = .019). In both trials, the lack of difference in OS may be in part because patients who relapsed after conventional therapy went on to receive HSCT and were salvaged by that regimen.


As the incidence of Hodgkin disease places it in an age group of mostly adolescents and young adults, many studies have pooled pediatric patients (<18 years) with older patients for study. A case-control series examining HSCT in children less than 16 years old at diagnosis compared with a population older than 16 years found progression-free survival was similar (39% vs 48%), as were most of the secondary measures and subgroup analysis between these older and younger patients. This study also confirmed chemotherapy-resistant disease is a poor prognostic factor in children and adults. A retrospective analysis of 51 children receiving autologous HSCT compared with 78 children receiving conventional salvage therapy did not find an advantage to HSCT, but may have been biased because the group proceeding to transplant had more adverse disease characteristics, a common issue with such retrospective analyses. Baker and colleagues reported on patients less than 21 years old at time of transplant for relapsed or refractory Hodgkin disease: 5-year OS was 43% and EFS 31%, and no difference was observed in 3 age brackets (<13 years, 13–18 years, and 19–21 years). As HSCT became more common, smaller case series were published in children from Spain, Germany, and Austria that again identified the presence of bulky or extranodal disease at time of HSCT as an independent poor prognostic factor in children.


The role of allogeneic HSCT has also been investigated for relapsed Hodgkin disease. Although early use of myeloablative regimens and allogeneic HSCT resulted in high transplant-related mortality (TRM) without much indication of benefit, some groups have reported disease regression with donor lymphocyte infusions (DLIs), suggesting a graft-versus-lymphoma effect is possible. There have been no randomized comparisons of allogeneic and autologous transplant for relapsed Hodgkin disease. A single-center study from the Fred Hutchinson Cancer Research Center comparing 53 patients receiving allogeneic HSCT with controls receiving autologous HSCT found a significantly lower relapse rate in the allogeneic recipients (45% vs 76%). EFS was not significantly different, and in the allogeneic transplant group the competing risk of TRM was high (53%). The role of reduced intensity conditioning (RIC) regimens in the allogeneic transplant setting is being investigated to reduce TRM and potentially expand the graft-versus-lymphoma effect. A recent report from Europe compared 89 patients receiving an RIC allogeneic HSCT with 79 patients receiving a traditional myeloablative regimen. About half of these patients had received a prior HSCT, and all were heavily pretreated. OS was superior in the RIC group (28% vs 22%) despite a higher relapse rate (57% vs 30%). This finding was likely a result of the significant reduction in TRM in the RIC group (23% vs 46%). A recurring theme in these patients is the poor prognostic indicators of chemotherapy-resistant disease and presence of bulky disease at time of transplant. This study continues a trend of earlier single-center reviews, and suggests that RIC allogeneic HSCT, either alone or coupled to an autologous HSCT, may have a role in the treatment of multiply relapsed patients with Hodgkin disease.


Although autologous HSCT is the treatment of choice for relapsed or refractory Hodgkin disease, the addition of newer agents such as monoclonal antibodies and tyrosine kinase inhibitors to conventional regimens has not been studied in a randomized fashion against HSCT. In addition, patients with chemotherapy-resistant disease or bulky disease at time of HSCT still do poorly. RIC allogeneic HSCT should be considered for patients who relapse following autologous HSCT, and more study is needed to further identify ways to reduce TRM and increase the potential of graft versus lymphoma.




Non-Hodgkin lymphoma


Pediatric non-Hodgkin lymphoma (NHL) consists mainly of Burkitt, lymphoblastic, diffuse large B cell, and anaplastic large cell lymphoma. Conventional chemotherapy remains the frontline treatment of choice, with long-term survival in the 60% to 90% range depending on histology. Relapsed disease carries a more dismal prognosis, and autologous HSCT has been investigated for these high-risk patients. A Children’s Cancer Group (CCG) study for relapsed lymphoma did not find a benefit for autologous HSCT for these patients, as EFS was not significantly changed compared with other salvage regimens. A comprehensive review by Gross and colleagues found that some patients with relapsed NHL can be salvaged by autologous or allogeneic HSCT. As with Hodgkin disease, chemotherapy-resistant disease and disease status at time of transplant significantly affect survival. As most single-center experiences include multiple types of NHL to acquire enough cases for review, separating effects within each subtype is difficult. A trend toward improved salvage with allogeneic HSCT in lymphoblastic lymphoma is seen, although this is biased by the greater number of patients who underwent this procedure compared with autologous HSCT. As the numbers of pediatric patients with relapsed or refractory NHL remain small, studying the role of autologous and allogeneic HSCT against conventional therapy is difficult.




Ewing sarcoma


Ewing sarcoma is the second most common bone tumor in children after osteosarcoma, and carries a 70% long-term survival for localized disease. The backbone of this therapy includes surgical resection, anthracycline and alkylator chemotherapy (typically doxorubicin and ifosfamide), and in some cases radiation therapy. Patients with metastases, however, have a worse outcome (4-year OS 39%) and survival after relapse is also dismal (10-year OS 10%). Escalation of therapy in patients with metastatic Ewing sarcoma with the core treatment agents ifosfamide, doxorubicin, and cyclophosphamide or addition of ifosfamide/etoposide to a standard regimen seemed only to increase short-term toxicity and secondary myelodysplasia.


In higher-risk patients with Ewing sarcoma, autologous HSCT has been investigated for poor prognostic groups such as patients with large, unresectable tumors, patients with metastatic disease, or that subset of stage-4 patients with metastases outside the lung (the highest risk group). A CCG study of 36 patients with Ewing sarcoma metastatic to the bone marrow at diagnosis investigated the efficacy of melphalan, etoposide, and total body irradiation (TBI) followed by autologous HSCT. This treatment led to no improvement in 2-year survival (20%) compared with conventional therapy. These disappointing results were replicated in 3 other studies, using allogeneic and autologous stem cell sources, with high rates of TRM raising further concerns. The ongoing EuroEWING-99 trial has a study question comparing autologous HSCT with intensified standard therapy for patients with a poor local response or with lung metastases. Patients are randomized after a standardized vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction phase. The data collection is ongoing.


For those patients who have relapsed Ewing sarcoma, the outlook is grim, with a 10% 5-year OS. In 2 single-center studies, 32 patients with relapsed Ewing sarcoma underwent megatherapy (26 with autologous HSCT, 6 with allogeneic HSCT). Fifteen of 32 patients were reported as long-term survivors, although they represent a rare subgroup that was able to achieve a second remission in this disease, and it is unclear if HSCT provides an advantage to intensified standard chemotherapy in these small highly selected groups. A common observation is that the outcome of megatherapy or autologous HSCT in the presence of gross residual disease is exceptionally poor (5-year OS 19%). Nevertheless, there are enough data to support design of studies comparing autologous HSCT with standard intensified therapy for high-risk and relapsed patients, and we look forward to the results of the EuroEWING-99 trial.




Rhabdomyosarcoma


Rhabdomyosarcoma is the most common sarcoma of childhood, and children with low- or intermediate-risk disease have excellent long-term survival rates with standard chemotherapy approaches. As with neuroblastoma, high-risk patients continue to do poorly despite intensification of nonmyeloablative chemotherapy as in the IRS-III and IRS-IV trials (5-year OS 30% for metastatic disease, group IV). In vitro and in vivo studies of relapsed rhabdomyosarcoma samples suggest sensitivity to melphalan, and based on this finding HSCT approaches to relapsed or high-risk rhabdomyosarcoma were designed. Of 98 HSCTs for relapsed or progressive rhabdomyosarcoma in children performed up to 1994 in Europe, the OS was not different from historical controls at 20%. Single-institution studies with various criteria to define high-risk rhabdomyosarcoma have replicated these data, with children in remission status receiving megatherapy achieving some degree of long-term OS, although it is unclear if this is superior to intensified conventional therapy. Although a randomized trial of autologous HSCT as a consolidation for high-risk patients without gross residual disease could be contemplated, there is little support for this approach in the current literature.




Neuroblastoma


Neuroblastoma is the most common extracranial solid malignancy of childhood, and has a broad spectrum of clinical presentations and behavior. Although low- and intermediate-risk neuroblastoma are mostly curable, high-risk neuroblastoma has proven refractory to conventional treatment modalities. Despite the unsatisfactory responses to conventional therapies, some improvements in outcome have been achieved through the escalation of therapeutic intensity. Although even the most intense conventional therapy results in long-term EFS of less than 40%, improvements can be achieved through the addition of consolidation therapy with high-dose therapies that exceed marrow tolerance. This improvement was originally achieved through the harvest, storage, and reinfusion of autologous bone marrow capable of reestablishing trilinear hematopoiesis, and later replicated using peripheral blood stem cells (PBSC). Even with this intensified consolidation therapy, outcomes still remained poor. However, the ability to collect adequate PBSC in small children, along with the decreased TRM associated with their use, has allowed for even more intense consolidation therapy by enabling tandem autologous HSCT. Early studies suggest that this is a feasible approach that may improve outcomes.


Early, Non-Randomized Studies


Having acquired the ability to safely harvest, store, and reinfuse HSC, investigators in the late 1980s and early 1990s began exploring the hypothesis that increased treatment intensity beyond marrow tolerance would improve survival in patients with high-risk neuroblastoma. Multiple early single-arm or retrospective studies suggested that autologous HSCT might improve the EFS of these patients, although none of the studies were randomized and may have been influenced by selection bias. The largest retrospective analysis was performed through the European Group for Bone Marrow Transplantation in 1997; 1070 transplants for high-risk patients with neuroblastoma were analyzed, and the 2-year survival among the group of patients who had reached an SCT procedure was 49%. Most relapses occurred within the first 18 months following transplant, and there were no survivors amongst the group of 48 patients who relapsed and underwent a second HSCT. Late relapses were found as long as 7 years from transplant.


Randomized Trials


The promise suggested by these early studies propelled prospective evaluation of autologous HSCT for high-risk neuroblastoma. The largest of the randomized, prospective studies was a phase III trial performed by the CCG. In CCG-3891, patients were randomized to a consolidation regimen consisting of autologous bone marrow transplant versus continuation chemotherapy. Following consolidation, patients were then randomized to biologic therapy with 13- cis- retinoic acid (a maturational agent) versus no further therapy. The study found that those treated with autologous HSCT had a significantly better EFS than those treated with chemotherapy alone. It was also noted that treatment with 13- cis -retinoic acid further improved outcome among patients without progressive disease. With an estimated 38% EFS 3.7 years from diagnosis in the best group, this study helped establish autologous HSCT followed by 6 months of oral cis- retinoic acid therapy as the new standard of care for these patients, and represented an important step forward in the treatment of high-risk neuroblastoma. Despite its important results, this study was subject to the challenges of a complex treatment plan and the 2 × 2 factorial design. Of 579 eligible patients, 379 underwent the first randomization, and 258 patients underwent the second, thereby reducing the population of patients being studied to approximately 50 patients in each of the 4 treatment groups. Other studies of autologous HSCT in high-risk neuroblastoma have since built on the results of CCG-3891. Conditioning regimens used in subsequent studies have varied widely, with the greatest difference being that some studies have used TBI in the conditioning regimen whereas others did not. There have been no randomized trials of the use of TBI during conditioning, and although it may improve outcomes, it also results in significant late effects in those who survive treatment. Thus, although the use of radiotherapy to the tumor bed is standard care in neuroblastoma, the use of TBI remains controversial. Overall, these studies have led to the current core standard for neuroblastoma treatment: 5 or 6 cycles of induction chemotherapy, surgery, radiotherapy (at a minimum to the tumor bed), and autologous HSCT followed by oral cis-retinoic acid. To this treatment, GD2-targeted immunotherapy may now be added based on recent data from the Children’s Oncology Group (COG) ANBL0032 study presented at the American Society of Clinical Oncology meeting in 2009, which showed a superior outcome in patients who received this immunotherapy in addition to cis-retinoic acid.


Tandem Transplantation


Given the evidence that dose intensity correlates with outcome, and that HDC with autologous stem cell rescue renders a statistically significant improvement in survival, it was logical to examine sequential courses of HDC with stem cell rescue, otherwise known as tandem transplant. Tandem transplantation allows for even greater dose intensity in consolidation, with the potential to introduce different active agents at each transplant. An early attempt to use this technique was complicated by unacceptable TRM, primarily related to extended periods of neutropenia following the transplants. Although initially discouraging, this study, like CCG-3891, was conducted using bone marrow as the stem cell source. Other stem cell sources, specifically PBSC, can provide more rapid engraftment and faster recovery times than bone marrow. The more rapid engraftment of PBSC results in decreased days with severe neutropenia and a shorter duration of mucositis, thereby resulting in a lower rate of infectious complications. With the high TRM found using bone marrow as the stem cell source for tandem transplantation, PBSC became an attractive alternative. Despite the challenges inherent in collecting PBSC from patients with high-risk neuroblastoma (young age at diagnosis, small size, and blood volume), clinicians can now safely, effectively, and routinely perform this procedure. Following the switch from bone marrow to PBSC, several groups have retested the tandem transplant approach, with more promising results. The largest of these studies was conducted for 6 years at 4 cooperating institutions. The study was designed using early collection of PBSC, CD34 selection as a purging method (discussed later) and 2 myeloablative regimens containing distinct agents: (1) carboplatin, etoposide, and cyclophosphamide, followed by (2) melphalan and TBI. TRM in this study was 6%, and included 2 patients who died of Epstein-Barr virus lymphoproliferative disease (EBV-LPD). Post-HSCT immunosuppression is discussed later. Longer follow-up of this treatment approach in a large phase II cohort has shown a 3-year EFS from diagnosis of consecutively enrolled patients of 55% (most recent update shown in Fig. 1 ). A second multiple-cycle autologous HSCT study, performed using 3 sequential HSCT procedures, found comparable results in 3-year EFS (57%), although there appeared to be instability of the curve out to 4 to 5 years. In that study, 19 of the 25 patients completed the second autologous HSCT and 17 went on to the third. Only 1 late TRM was observed. Based on these promising results, the current open phase III COG trial, ANBL0532, is testing single versus tandem transplant as consolidation therapy for high-risk neuroblastoma.




Fig. 1


Kaplan-Meier curves showing OS and EFS for consecutively treated patients undergoing tandem autologous HSCT for high-risk neuroblastoma. The patients were conditioned with carboplatin/etoposide/cyclophosphamide for the first autologous HSCT procedure, followed by melphalan/TBI for the second. A ) OS from diagnosis, ( B ) EFS from diagnosis, and ( C ) EFS from diagnosis stratified by MYCN (nMYC) amplification.

Modified from Fish JD, Grupp SA. Stem cell transplantation for neuroblastoma. Bone Marrow Transplant 2008;41:162; with permission.


Processing of Stem Cells


In addition to increasing dose intensity, graft manipulation has been used to attempt to improve survival following autologous HSCT in neuroblastoma. Engineering of the HSC graft is possible to remove or expand desired cell populations. The most researched manipulation in the context of neuroblastoma has been purging of malignant cells before the infusion of the HSC product. Research in the 1990s suggested that clonogenic tumor cells can be infused with an HSC graft, and that these cells can result in relapse of the malignancy. This finding led to trials in neuroblastoma addressing the question of whether purging stem cell products of tumor cells could further improve posttransplant overall and disease-free survival. There are 2 methods to purge an HSCT product of tumor cells: either positive selection of HSC, leading to the exclusion of tumor cells, or negative selection designed specifically to remove malignant cells. Positive selection of CD34 expressing cells is the primary technique available to most stem cell laboratories. CD34 is an antigen expressed on HSC and progenitors of all hematopoietic lineages, and positive selection of CD34 would result in the exclusion of neuroblastoma from the graft, assuming that the neuroblastoma cells themselves do not express CD34. Concerns have indeed been raised that some neuroblastoma cells may express either CD34, or surface epitopes cross-reactive with the anti-CD34 monoclonal antibodies necessary for the selection process. Our data have not confirmed this hypothesis, and we, along with others, have used CD34 selection as a purging technique for PBSC products in the clinical setting.


Automated processes are available that are capable of selecting the CD34+ cell population away from the 99% of peripheral blood mononuclear cells that are irrelevant for engraftment, including T cells and any tumor cells that do not express CD34. Of these automated technologies, the Isolex 300i device (Baxter, Deerfield, IL, USA) is approved by the US Food and Drug Administration, and the Miltenyi CliniMACS device is approved in Europe and may become available in the United States. In negative selection, the most widely used technique in neuroblastoma has been antitumor monoclonal antibodies followed by a magnetic depletion step. Although the evidence suggests that purging of bone marrow may be important, PBSC are less likely to contain tumor cells than bone marrow, and no study to date has shown that purging itself improves outcome. The COG has assessed whether graft manipulation through negative selection improves survival. COG A3973 is a recently completed, phase III, randomized comparison of purged versus unpurged PBSC given in the context of autologous HSCT for high-risk neuroblastoma. Data from this trial have yet to be published, but preliminary analyses have shown no advantage for patients receiving a purged PBSC product (S Kreissman and W London, unpublished data, 2008). The 2-year EFS was 51% in the unpurged group and 47% in the purged group ( P = .47). The overall estimated 3-year EFS was 40%.


In 2010, the standard treatment of a patient with newly diagnosed high-risk neuroblastoma is based on the premise that maximal tolerable intensity of therapy yields maximal positive outcomes. The clinical trials outlined earlier have resulted in a therapeutic backbone of multicycle induction, PBSC collection early in induction, testing of the PBSC product for neuroblastoma contamination, as complete surgical resection as possible without organ sacrifice, autologous HSCT, and local radiotherapy, followed by biologic therapy and immunotherapy. It is an imposing package, and in the quest to improve outcomes further, the current phase III COG ANBL0532 trial is testing single versus tandem transplant as consolidation therapy. Although maximum tolerable intensity of cytotoxic therapy has been achieved, the outcomes for patients with high-risk neuroblastoma remain poor, with a 5-year OS less than 50%. Having reached an effective limit in chemotherapeutic intensity with tandem transplant, future trials need to focus on targeted therapies or immunotherapy in the hope of improving outcomes for children afflicted with this disease.


High-Dose mIBG with Stem Cell Rescue


The neuroendocrine nature of neuroblastoma makes it amenable to therapy with radiopharmaceutical agents also. Arising from the adrenal medulla, 90% to 95% of neuroblastomas show characteristic uptake of catecholamines and their derivatives, making them attractive radiopharmaceutical agents. Metaiodobenzylguanidine (mIBG) is an aralkylguanidine analog of catecholamine precursors, first reported in 1979, that can be labeled with 123 I or 131 I and imaged with a γ-camera. The first report using mIBG for diagnosis and localization of neuroblastoma was in 1985. Since that time, diagnostic imaging with [ 123 I-m]IBG has become the standard of care.


[ 131 I-m]IBG is a higher-energy releasing isotope that has been used for therapy for neuroblastoma since the mid-1980s. A review of the literature in 1999 showed an objective response rate to [ 131 I-m]IBG of 35% across multiple small studies, and a phase I study of its efficacy showed a response rate of 37% in children with relapsed neuroblastoma. The dose-limiting toxicity of the [ 131 I-m]IBG is hematologic, although the marrow failure associated with high-dose [ 131 I-m]IBG can be overcome using stem cell rescue. Building on these findings, several groups began to incorporate high-dose [ 131 I-m]IBG into the conditioning regimen for autologous HSCT. Initial, small-scale pilot studies showed the tolerability of high-dose [ 131 I-m]IBG combined with standard myeloablative chemotherapy. This finding led to a larger, phase I study that again reported good tolerability of this combination in patients with refractory neuroblastoma but also reported an OS of 58%. A phase II study combining high-dose [ 131 I-m]IBG and intensive chemotherapy as consolidation is under way for patients with high-risk neuroblastoma. Novel modalities for using this unique radiopharmaceutical in the treatment of neuroblastoma promise further improvements in outcomes for patients with high-risk disease.




Allogeneic HSCT


Allogeneic transplant for solid tumors of childhood has been studied in a limited fashion and is rarely pursued, which may partly be a result of the neuroblastoma experience, in which allogeneic marrow sources were not superior to purged autologous sources (see later discussion). No convincing evidence of any graft-versus-solid-tumor effect has been shown in pediatric patients, although case reports continue to be suggestive. In contrast, some of the earliest reports of allogeneic graft-versus-solid-tumor reports were in adult metastatic renal cell carcinoma, in which 4 of 50 patients receiving myeloablative therapy and allogeneic stem cells were long-term survivors. A few other reports of allogeneic activity against adult tumors exist, including colon carcinoma, ovarian carcinoma, and prostate carcinoma. In a review of these adult case reports and other small series, Ringden and colleagues comment that the allogeneic effect may be a blunt application of immunotherapy that could be much more specifically applied with monoclonal antibodies without TRM.


The potential benefit of immunotherapy or cellular therapy for solid tumors should not be discounted; however, pure myeloablation and allogeneic reconstitution does not seem to provide any specific benefit for pediatric solid tumors in the face of the considerable risk of graft-versus-host disease (GVHD) and TRM. A recent report from Japan using a model of a murine bladder tumor, RIC, and allogeneic reconstitution followed by DLI showed some antitumor effect. A recent case report from France observed that an adult patient undergoing RIC and allogeneic transplant for acute myelogenous leukemia had concomitant regression of a malignant renal tumor.


Similarly, the potential to harness an immunotherapeutic effect has led some groups to study allogeneic HSCT for high-risk or relapsed neuroblastoma. A case report in 2003 described a patient in whom residual disease noted following a haploidentical HSCT fully resolved 3 years later, hinting at a potential graft-versus-neuroblastoma effect. However, although the promise of a graft-versus-malignancy effect has been well described in allogeneic transplant for liquid tumors, it has yet to be convincingly shown in the setting of solid tumors. Two studies published in 1994 compared allogeneic with autologous HSCT for high-risk neuroblastoma. The first compared the outcomes of 20 patients who underwent a single, human leukocyte antigen (HLA)-matched sibling donor transplant with 36 patients who underwent autologous transplants following identical TBI-containing conditioning regimens. Four of 20 allogeneic patients experienced TRM, compared with 3 of 36 autologous patients (P = .21). The relapse rate among allogeneic HSCT patients was 69%, compared with 46% for autologous HSCT patients (P = .14), and the estimated progression-free survival rates 4 years after HSCT were 25% for allogeneic HSCT patients and 49% for autologous HSCT patients (P = .051). A second case-controlled study compared 17 allogeneic and 34 autologous cases. It found no difference in progression-free survival (35% and 41% at 2 years, respectively). Although these initial results do not show any clear benefit of allogeneic versus autologous HSCT for high-risk neuroblastoma, the advent of RIC regimens has provided the possibility that reduction of TRM allows for the detection of a therapeutic benefit. The limited data available to date indicate that there is no current role for allogeneic transplant for solid tumors in pediatric patients outside the context of well-designed clinical trials.

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Oct 3, 2017 | Posted by in PEDIATRICS | Comments Off on Autologous and Allogeneic Cellular Therapies for High-risk Pediatric Solid Tumors

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