eMedicine Specialties > Pediatrics: General Medicine > Oncology

Immunotherapeutic Targeting

Author: Crystal L Mackall, MD, Deputy Branch Chief, Head of Immunology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health
Coauthor(s): Christian M Capitini, MD, Clinical Fellow in Pediatric Hematology/Oncology, National Cancer Institute and Johns Hopkins Hospital
Contributor Information and Disclosures

Updated: Sep 24, 2008

Introduction

The backbone of cancer therapy in pediatric oncology has been stepwise integration of multimodality therapies (eg, chemotherapy, surgery, radiation therapy) into carefully designed treatment regimens tested sequentially through multicenter randomized trials. Although chemotherapy has been effective in eradicating micrometastatic disease in some conditions and remains a principal determinant of success, the toxicity associated with current cytotoxics is substantial, and current agents have not proven curative in several clinical groups. Hence, the need is growing for the development of effective, alternative anticancer therapies for use in children with tumors. 
 
Dramatic progress in technology has improved our understanding of the basic biology of tumor immunology, and immune-based therapies represent one approach that could be integrated into current multimodal regimens to eradicate micrometastatic disease. Immunotherapeutic targeting of cancers is an attractive, novel modality that could be used either in conjunction with conventional therapies or separate from these therapies. Evidence currently suggests that the mechanisms responsible for resistance to cytotoxic agents generally do not confer resistance to immune-mediated mechanisms of tumor-cell killing.1,2,3,4,5,6
 
The immune system participates in immunosurveillance of tumors, as evidenced by the following:

  • Patients develop spontaneous innate and acquired immune responses to their tumors.7
  • One positive prognostic indicator of patient survival in many histologies is infiltration of lymphocytes within a tumor.7
  • Immunosuppressed transplant recipients display higher incidences of nonviral tumors than age-matched immunocompetent controls.7
  • Various murine studies have reported that both spontaneous and carcinogen-induced tumors occur more frequently in mice that lack various elements of innate and adaptive immunity.8
  • Tumors are less able to survive in immunocompetent mice.7  

This last observation provides evidence that the development of immune-evasive properties occurs in response to immune pressure early during the period of oncogenesis. Merchant and colleagues also suggest that T-cell–depleting cancer therapies may eliminate beneficial immune responses and that immune reconstitution of patients with lymphopenic cancer could prevent metastatic recurrence of solid tumors.9

In summary, current models hold that tumor antigens are present and induce immune reactivity during incipient tumor growth and that tumors subsequently develop properties to evade these immune responses. The challenge to the current field is to elucidate the biology of host-tumor interactions at the time of clinical presentation with cancer and to develop approaches that diminish the capacity for tumors to evade immunity and amplify host antitumor immune responses. In pediatric oncology, the ability to apply such therapies during a period of minimal residual disease is compelling and can often be accomplished with modern multimodality therapies.
 
This article begins with a brief review of the historical background of immunotherapy for cancer and then addresses the central scientific principles that serve as the basis for the development of immunotherapies against tumors, with emphasis on the recent clinical experience in pediatric oncology using each approach.

Innate Immune System

William Coley, MD, is regarded as the father of cancer immunotherapy.10 Coley was a pioneering surgeon who practiced medicine at Memorial Hospital in New York City from 1890-1936.11 During this time, he focused on the treatment of sarcomas and developed a firm belief that activation of endogenous immune responses could induce remission of tumors. This conviction arose from reports and direct observations of spontaneous tumor remissions that were temporally related to bacterial infections and were primarily observed in patients with sarcoma in his practice. Coley subsequently produced crude bacterial extracts that were eventually termed "Coley toxins" and were administered to patients with cancer. In some cases (albeit relatively infrequently), dramatic antitumor effects were observed. Ewing sarcoma was one of the tumors in which Coley observed antitumor responses using this approach.10,12
 
During the same period in which Coley was observing dramatic tumor responses using Coley toxins, the spectacular radiosensitivity of Ewing sarcoma was observed by James Ewing, MD, who was the physician-in-chief at MemorialHospital. This led to a rivalry between advocates of immunotherapy, delivered in the form of "Coley toxins," and advocates of radiotherapy (such as Ewing).11 For various reasons, not the least of which was difficulty in standardizing the toxins, immunotherapy was eventually abandoned in favor of cytotoxic radiotherapy, a legacy that persists to this day.
 
Today, bacteria are known to be potent inducers of the body's first-line defense, the innate immune system. Activation of innate immunity can not only induce direct antitumor effects but can also boost adaptive immunity (especially T-cell responses) and assist in improving tumor antigen presentation.13  As knowledge of the innate immune system has advanced, the possibility of generating a modern Coley toxin that could incorporate specific activators of innate immunity has increased.
 
Innate immunity refers to cellular components that serve as the first-line immunologic defense that participates in rapid, nonselective protection without resulting immunologic memory. Stimulation of toll-like receptors (TLRs), which recognize highly conserved structural and molecular patterns on pathogens, are critical to initiating activation of antigen-presenting cells (APCs), which have recently been found to be involved in the efficacy of radiation therapy.14 Coley toxins likely work through stimulation of TLRs; currently, many investigators seek to optimize TLR activation as a means for potent, reproducible activation of innate immunity.
 
Toll-like receptor activation
 
Thirteen TLRs have been identified in humans, each binding one or more specific TLR ligands.15  TLRs can be activated by proteins that are released by or associated with pathogens (ie, lipopolysaccharide, double-stranded RNA, double-stranded DNA) or released by proteins exposed by tissue damage. Although pathogen-derived TLR ligands are well characterized, elucidation of TLR ligands derived from self-tissues continues. 
 
The therapeutic potential of TLR-targeted therapies has been realized in two adult cancers using the cell-wall skeleton of Bacillus Calmette-Guérin (BCG-CWS), a TLR2 and TLR4 agonist, in the treatment of bladder cancer,16 and using imiquimod, a TLR7 agonist, in the treatment of basal cell cancer.17 Clinical trials are ongoing in several other adult malignancies, but preliminary results suggest that these may not be sufficient as single agents to induce regression of established bulky tumors.17   
 
Thus far, such approaches have not made their way into pediatric oncology clinical trials; however, this may be possible. Several animal models of pediatric tumors have shown responses to CpG oligodeoxynucleotides, a TLR9 agonist, including acute myelogenous leukemia (AML), lymphoma, neuroblastoma, and rhabdomyosarcoma.18  Aluminum salts, an adjuvant with TLR4 agonistic properties, have been engineered into vaccines used in children, such as the human papilloma virus vaccine, to augment immune responses and prevent development of secondary cervical cancer.17
 
Tumor cells can also release or expose damage-associated molecular patterns, which include lipids and lipopeptides, proteins, and nucleic acids that bind to TLRs and cause activation of macrophages and dendritic cells (DCs).17 The release of inflammatory mediators by damaged cells also plays a central role in amplifying and directing specific T-cell responses. Recent studies have investigated the contribution of such damage-associated molecular patterns in the antitumor effects seen with more conventional cytotoxic therapies. For instance, deficiency of TLR4 compromises the efficacy of chemotherapy or radiotherapy in vivo.19 Moreover, tumor irradiation has been recently hypothesized to activate effectors of innate immunity through the induction of tumor-cell apoptosis and the release of endogenous TLR agonists, such as heat-shock proteins, uric acid, or high-mobility group box protein 1 (HMGB1). Whether this relates solely to release of damage-associated molecular patterns by dying eukaryotic cells or is an indirect effect of mucosal damage with systemic seeding of bacteria remains unclear. 
 
Whole body irradiation was recently shown to increase bacterial translocation and circulating levels of the TLR4 agonist lipopolysaccharide.14 This platform has been shown in a preclinical model to enhance the effectiveness of adoptively transferred CD8+ T cells in tumor-bearing, lymphodepleted mice, leading to improved tumor regression, whereas tumor-bearing mice deficient in TLR4 do not benefit from whole body irradiation.20 Thus, although radiation may have been traditionally viewed as a purely cytotoxic therapy to shrink tumors, it may also have significant immunomodulatory properties.
 
Danger signals in rhabdomyosarcoma and other tumors
 
The release of inflammatory mediators (alarmins) as tumors die off can lead to immune responses against self-molecules. HMGB1 is one such nuclear protein that binds the receptor for advanced glycation end products (RAGE) TLR2 or TLR4.21,22 Tumor cells that undergo apoptosis in vitro in response to anthracyclines can be picked up by dendritic cells through TLR4 and lead to long-term tumor protection without addition of adjuvants.
 
The relevance of this in pediatric oncology has been demonstrated in rhabdomyosarcomas, in which preclinical data have shown that HMGB1 stimulates myogenesis through RAGE; this tumor may reduce expression of RAGE as a means of survival.23 The implications are that alarmins are a byproduct of tumor cell death, are purposefully underexpressed by tumors to avoid detection by the immune system, and are a potential novel target for immunotherapy.
 
Muramyl tripeptide phosphatidylethanolamine in osteosarcoma
 
MTP-PE is an analog of muramyl dipeptide, a substance contained within the cell wall of mycobacteria that has immune-activating activity. When MTP-PE is encapsulated in multilamellar liposomes (L-MTP-PE), it is efficiently delivered to the liver, spleen, lung, nasopharynx, and thyroid following intravenous infusion.3  
 
L-MTP-PE can bind to TLR4 on monocytes and macrophages, leading to activation of these cells and promoting antitumor activity.24 Presumably, the antitumor effects of MTP-PE are mediated via release of interleukin (IL)-1β, IL-6, IL-8, nitric oxide, prostaglandin E2 (PGE2) and tumor necrosis factor alpha (TNF-α).25 The exact mechanism whereby monocyte/macrophage activation and cytokine release results in tumor cell death remains incompletely understood.
 
MTP-PE administration has been primarily studied in pediatric patients with osteosarcoma, a disease that frequently metastasizes to the lung and a disease in which micrometastases cause treatment failure in almost 40% of patients despite administration of multiagent chemotherapy.
 
In a phase II trial, MTP-PE prolonged disease-free survival in a group that received 24 weeks of therapy.3 In addition, peripheral fibrosis, inflammatory cell infiltration, and neovascularization were observed in metastases from recipients of MTP-PE but not in control subjects. Thus, this trial suggested that L-MTP-PE is an active biologic agent that can produce a survival benefit in this patient population.25
 
Further investigation of MTP-PE in patients with osteosarcoma was undertaken in a phase III trial, in which improved survival rates were noted in patients who received ifosfamide-containing cytotoxic drug therapy (ie, cisplatin, methotrexate, adriamycin and ifosfamide) with MTP-PE but were not observed in the those receiving MTP-PE without ifosfamide.25 Notably, this study was configured with a factorial design, wherein patients were randomized to 1 of 4 arms, with the intent to compare the use of 3 standard drugs versus 4 standard drugs and, in a separate question, to answer whether the addition of MTP-PE improved outcome. Because no benefit was observed when MTP-PE was used in the absence of ifosfamide, which was an unexpected finding, the investigators were not able to conclude a definitive benefit from MTP-PE as a single agent. Thus far, MTP-PE has not been approved by the US Food and Drug Administration (FDA) for use in osteosarcoma and, therefore, is not readily available for treatment of patients with this disease.
 
Natural killer cell-killer immunoglobulinlike receptor mismatch
 
Natural killer cells are lymphoid cells that are part of the innate immune system because they do not express clonotypic receptors nor mediate immunologic memory. However, they are potent mediators of antitumor effects because they identify and kill tumor cells in the absence of inflammatory signals and can directly reject tumors. Natural killer cell activation is a complex process, with interactions among various activating and inhibitory natural killer cell receptors and various ligands determining whether natural killer cells activate and kill targets.26 The major natural killer cell inhibitory receptors are the killer immunoglobulinlike receptors (KIR), which are expressed on the surface and inactivate the natural killer cell when it encounters a cell that expresses self-major histocompatibility complex (MHC) class I. Activating receptors include NKG2D, which binds MICA or MICB on tumor cells, and Fc receptors, which bind the Fc region of antibody molecules.
 
Several clinical trials have shown that adult patients with AML who underwent bone marrow transplant and were mismatched for natural killer cell-KIR and MHC displayed improved survival.27 This success appears to be contingent on using a T-cell–depleted transplant, perhaps because of the absence of immunosuppressive agents that may interfere with the natural killer cell–mediated effects. A phase II trial through the Children's Oncology Group is currently exploring the efficacy of allogeneic natural killer cell-KIR mismatched transplants in children with relapsed, refractory, or newly diagnosed AML, and recruitment is ongoing (see Clinicaltrials.gov).

Limitations of Innate Immune System Activation

Although innate immune effectors can clearly mediate antitumor effects, elements of innate immunity may also contribute to tumor growth. Much recent interest has been focused on the interaction between inflammation and carcinogenesis. Especially in adult carcinomas, chronic inflammation can give rise to cancer, whereas anti-inflammatory therapies can prevent cancer. Thus, although specific activation of innate effectors (eg, monocytes, macrophages, eosinophils) can induce potent killing of tumor cells,28,1,29,30 ample evidence also implicates tissue macrophages as contributors to the immunosuppressive microenvironment within tumors themselves and, thus, potential contributors to tumor growth. 
 
M1 versus M2 macrophages
 
To further the complexity, macrophage differentiation has been characterized as proinflammatory (the so-called M1 macrophage) and anti-inflammatory (the so-called M2 macrophages). Tumor-associated macrophages primarily appear to consist of the M2 variety and are known to localize into hypoxic regions of tumors and to secrete various immunosuppressive cytokines. M2 macrophages also promote tumor progression by facilitating angiogenesis and invasion.31 In many animal models, macrophage depletion actually results in diminished tumor cell survival, increased tumor rejection, or both. Notably, pediatric tumors show a predominance of macrophage infiltration, suggesting that the immunosuppressive macrophage may have particular importance in pediatric solid tumors.32
 
Type I versus type II natural killer T cells
 
Natural killer T cells represent another class of cells in which a dichotomy is observed; some subpopulations induce immune activation and antitumor effects, whereas very similar but distinct populations can actually contribute to tumor growth and progression.33 For instance, the type I (classic) natural killer T cells express the semi-invariant T-cell receptor (TCR) using a unique TCR Vα14Jα18 chain in the mouse and a Vα24Jα18 chain in the human. This TCR recognizes the glycolipid α-galactosylceramide (αGalCer) in association with a nonclassical MHC class I molecule called CD1d. Type I natural killer T cells have been shown to protect against methylcholanthrene-induced sarcomas in vivo, and this effect depends on αGalCer and IL-12 production by DCs.34,35,36 These cells appear to produce interferon γ, a cytokine which then recruits natural killer cell and CD8+ T cells to the tumor, leading to lysis.

Type II (nonclassic) natural killer T cells also bind CD1d but lack the Vα24Jα18 chain, have many different TCRs, and, with rare exception, do not recognize αGalCer. This subset is poorly understood but is generally thought to be suppressive of tumor immunosurveillance.
 
Because of the success of natural killer T cells in eliminating tumors in preclinical mouse models, clinical trials were performed using αGalCer-pulsed DCs and natural killer T cells in[patients with lung cancer. Neither administration of the DCs nor adoptive transfer of autologous natural killer T cells activated with αGalCer and IL-2 yielded responses but were well tolerated in phase I trials.37,38 Humans generally have lower frequency of natural killer T cells, but biologic differences between natural killer T cells in mice and those in humans may explain the disparity; further trials are needed.
 
Myeloid-derived suppressor cells
The role of myeloid-derived suppressor cells (MDSC) as an important component of the immunosuppressive microenvironment of tumors is becoming more appreciated. Indeed, tumor growth results in expansion of this subset, causing a reduction in arginine levels and a subsequent increase in nitric oxide in tumors, which inhibits T-cell activation and antigen-specific responses. Therapies that inhibit cyclooxygenase-2 enzyme activity, inhibit MDSC function, or cause MDSC differentiation (ie, all-trans retinoic acid) are being explored in preclinical models.39

Adaptive Immune System

The adaptive immune system is composed of T cells and B cells that undergo specific recognition of foreign antigens and generate immunologic memory. T cells are lymphoid cells that are generated in the bone marrow but undergo maturation in the thymus. They only recognize foreign peptides when presented with a self-major histocompatibility complex (MHC) molecule; this interaction is the first signal needed to activate a T cell. These cells also require stimulation by a second signal, a costimulatory molecule provided by professional antigen-presenting cells (APCs), typically dendritic cells (DCs), that instruct T-cells to become activated against antigens expressed in the milieu. In this regard, researchers have designed vaccines that provide these 2 signals to target a tumor-associated antigen. Other than their direct cytotoxic effects against tumors, T cells can also secrete various cytokines that recruit other components of the immune system. 
 
B cells are lymphoid cells that serve as professional APCs but also secrete antibodies in response to a foreign antigen. Generation of monoclonal antibodies against tumor-associated antigens and receptor tyrosine kinases has led to various targeted therapies that have improved tumor responses even in tumors that failed conventional therapies.

T-cell–Based Therapies

Perhaps the most effective form of immunotherapy of cancer is the graft-versus-leukemia effect mediated by allogeneic T cells following bone marrow transplantation for leukemia. The ability of transferred T-cells to eradicate leukemia highly depends on the type of leukemia, the degree of tumor burden, and the rate of disease progression. Careful clinical trials are necessary to target tumor histologies and tumor burdens most receptive to immune-based therapies, and creative combination strategies are likely to be needed to enhance the effectiveness of T-cell–mediated antitumor effects in most clinical settings.
 
Graft-versus-leukemia after bone marrow transplantation
 
Development of bone marrow transplantation as a clinical approach to malignancy initially rested on the assumption that high doses of chemotherapy were necessary to eradicate relatively chemoresistant leukemia. In this paradigm, the marrow graft served only to rescue marrow function that was irreversibly ablated by high-dose therapy or irradiation. However, clinical evidence accumulated over the past 25 years has shown that an important component of the graft-versus-leukemia effect in bone marrow transplantation is related to an immunologic reaction that occurs between donor T cells contained in the marrow graft and residual tumor cells that remain following high-dose chemotherapy.40,41,42,43,44,45
  • Patients who develop some evidence of graft-versus-host-disease (GVHD) experience a lower incidence of leukemic relapse.46
  • Increased intensity of immunosuppression used to prevent GVHD is also associated with increased leukemic relapses after bone marrow transplantation.42,45
  • T-cell depletion of the marrow graft increases the rate of leukemic recurrence especially in chronic myelogenous leukemia (CML) and myelodysplasia/acute myeloid leukemia (AML).47,48,49
  • Leukemic relapse can sometimes be successfully treated by the infusion of donor lymphocyte infusions (DLIs) composed of peripheral blood T cells that can reinduce remission.50,51,52,53
Perhaps the most important principle gleaned from the clinical experience is the potency with which T cells can permanently eradicate aggressive, recurrent, and chemoresistant leukemic cells. Several other lessons are also pertinent. Immune responses can sometimes occur at a relatively slower tempo than that observed with cytotoxic therapies. For example, in CML, detection of molecular evidence of leukemia for at least 6-9 months after bone marrow transplantation is not uncommon, with gradual resolution of molecular evidence of residual leukemia occurring over 1-2 years.54
 
A second important principle is that all leukemias are not equally susceptible to the graft-versus-leukemia effect. For instance, DLIs induce complete responses in 60-80% of patients with stable chronic-phase CML; the response rate is approximately 30% in accelerated-phase CML, and less than 20% of patients in CML blast crisis respond.52 However, DLIs have had less promising results in other leukemias, including 15-29% response rates in AML and less than 15% in acute lymphoblastic leukemia (ALL).55 Thus, polyclonal T cells mediate antitumor responses with a wide range of efficacy, even within a given tumor. The reasons for the differences in susceptibility are not well understood but no doubt hold important clues to the understanding of immune-based mechanisms of antitumor activity.
 
A growing body of literature suggests that T cells can also exert antitumor effects in some solid tumors, including a 25% response rate in renal cell carcinoma.56,57,58 Whether similar activity is observed against pediatric solid tumors is unknown, but a few institutions have begun trials, ranging from adoptive immunotherapy of vaccine-primed T cells after chemotherapy to allogeneic stem cell transplants for pediatric patients with solid tumors.59,60,61,62,63
 
New approaches in bone marrow transplantation are also focusing on ways to diminish the toxicity of bone marrow transplantation by reducing myelosuppression of the preparative regimen while preserving the antileukemic effect that is mediated by T cells contained within the graft.64 Thus, bone marrow transplantation appears to be evolving away from high-dose myelosuppression and toward adoptive immunotherapy, thus creating an environment that can enhance the immune-mediated effects.
 
Tumor vaccines
 
As discussed above, the efficacy of graft-versus-leukemia in eradicating leukemia illustrates the potential of T cells as effectors of antitumor activity in allogeneic settings. To exploit T-cell reactivity to autologous malignancies, existent weak tumor–directed immune responses must be amplified to result in meaningful antitumor effects. This is particularly challenging for cancer because tumor antigens frequently represent overexpressed self-antigen, for which the quality and quantity of antigen-reactive T cells is limiting.

Therapeutic tumor vaccination is one strategy that initiates a dynamic process of activating the host's own immune system against a tumor antigen. The immunologic tolerance induced by tumor antigens during the course of primary tumor growth is not absolute and can be overcome through specific immunization with professional APCs or by transducing tumor cells with cytokine or costimulatory receptor-encoding genes.65  Although tumor vaccines alone do not induce clinically meaningful antitumor effects in patients with measurable tumor burdens, the usefulness of such immune-based therapies is likely to be optimal in patients with minimal residual disease.66,67  
 
Randomized studies comparing outcomes following tumor vaccination for patients with high risk of disease recurrence have only rarely been conducted. Of the 9 vaccines tested in phase III trials thus far, only one showed a reduction (31%) in the hazard rate for progression in asymptomatic, metastatic, hormone-refractory prostate cancer: sipuleucel-T (Provenge), which is composed of autologous APCs that express prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor (GM-CSF).68  The trial was not designed to look at overall survival as a primary endpoint, but the group who received Provenge had a 4.5-month increase in overall survival.

Limitations of Adaptive Immune System Activation

Various challenges face the development of immune-based therapies for childhood cancer. One challenge to the development of vaccines for pediatric tumors is the rarity of these tumors; hence, the ability to effectively test vaccine strategies directed at common immunodominant antigens is difficult. Although identification of a particular peptide that is capable of inducing antitumor effects may be possible in patients with a given MHC and pediatric tumor, this is likely to occur in only a few patients per year. Thus, the ability to test such complicated and specific therapies in rare tumors is limited, and the clinical applicability of using specific targeted epitopes is small. Hence, enthusiasm is greater for targeting more public tumor antigens that are shared across different tumor types and for developing immunizing approaches that can be used across human leukocyte antigen (HLA) types, such as whole protein or whole cell techniques. 
 
Second, because dose-intensive chemotherapy is a standard component of almost all therapies for pediatric tumors, integrating T-cell–based therapies into existing therapies requires attention to the important changes in T-cell homeostasis induced by lymphopenia, which impacts the effectiveness of T-cell–based immunotherapy. Although pediatric patients have more rapid recovery of immunity than adults following T-cell–depleting chemotherapy, immune recovery in pediatric patients following dose-intensive chemotherapy still usually takes at least 6-12 months.69,70,71,72,73,74
 
Recent studies have demonstrated that lymphopenia can provide a fertile milieu for immunotherapy; however, this is not universally true. In general, lymphopenic hosts appear to provide a reasonably fertile environment for adoptive immunotherapy. Immunization undertaken in the context of lymphopenia can be more effective than when undertaken in T-cell–replete hosts if adequate T-cell numbers and effective APCs are provided.75 Results of a study of patients with Ewing sarcoma and alveolar rhabdomyosarcoma were recently reported; adoptive T-cell transfer was administered, with peptide-pulsed DC vaccines undertaken during the period of lymphopenia that immediately followed dose-intensive chemotherapy.73  In this study, the overall survival for patients with metastatic or recurrent Ewing sarcoma or alveolar rhabdomyosarcoma treated with adoptive T-cell transfer and DC vaccination was 43% at 5 years. Interestingly, although the patients showed minimal measurable immune responses to the peptide-based vaccine, which targeted the translocation breakpoint junctions, they were immunocompetent to influenza vaccination within 3 months following completion of chemotherapy.
 
Third, the optimal technique for tumor vaccination has not been defined. Peptide-based vaccines have been successfully used by some groups and are known to be simple to produce, relatively inexpensive, and safe.76 However, as discussed above, such an approach requires identification of a tumor-specific or tumor-associated peptide, which is challenging because of the rarity of pediatric tumors. 

For neuroblastoma, peptides derived from the amplification MYCN oncogene have been shown to be capable of inducing immune responses ex vivo and capable of lysing neuroblastoma cells in patients with HLA A1+ tumors; thus, this target could potentially be clinically exploited in future studies.77 Peptide-based DC vaccines were developed to target the translocation breakpoints in Ewing sarcoma and alveolar rhabdomyosarcoma, but no clinical responses were observed.78 WT1 is a zinc finger transcription factor that is overexpressed in various hematologic and solid tumors, and peptide vaccines that express WT1 have yielded clinical responses in various adult malignancies.79  It has recently been found to be a target antigen for the graft-versus-leukemia effect.80 Trials are now underway using vaccines that express WT1 in children (see Clinicaltrials.gov).
 
An alternative approach is to use components of the tumor cells themselves to potentially immunize patients of any HLA type to various potential antigens available within the tumor. For example, Geiger et al used tumor lysate–pulsed DCs to immunize patients with pediatric solid tumors and reported some preliminary evidence for antitumor effects.81,60 Neuroblastoma cells have also been transduced using complementary DNA-encoding cytokines and have been subsequently used to immunize patients.82,83 The rationale for this approach is based on data that demonstrate that stimulatory cytokines can generate immune responses that show cytolytic activity for both cytokine-secreting and non–cytokine-secreting cells that bear the same antigens.

Clinical evidence for antitumor activity was observed using autologous neuroblastoma cells transduced to secrete interleukin (IL)-2, resulting in a 20% objective tumor response and 30% stable disease rate in 10 patients.84 As a result of the technical difficulties of reliably generating gene-transfected tumors in patients, these investigators have also explored the use of allogeneic neuroblastoma cells transduced with IL-2.82 Neither treatment produced any toxicity aside from local induration at the site of tumor injection. Repeat studies attempted to improve the outcome of this approach by cotransfecting the complementary DNA–encoding cytokines with the chemokine lymphotactin in autologous neuroblastoma cells; a few complete and partial responses were noted in one trial, but no responses were noted in the other.85,86
 
The potential of using master cell banks of allogeneic tumors as immunogens is compelling because of the ability to generate an "off the shelf" reagent that can be applied across patients. Whether such allogeneic tumor cells lines provide a more effective or less effective immunogen remains to be determined.

Cytokines and Growth Factors

Future studies will seek to combine T-cell–based vaccination protocols with other modalities to amplify the magnitude of the immune response. For instance, various adjuvants, such as granulocyte monocyte-colony stimulating factor (GM-CSF) and toll-like receptors (TLRs), can be used to more optimally activate antigen-presenting cells (APCs); these can potentially result in more effectively activated or expanded T cells. 

Alternatively, cytokines, growth factors, and costimulatory molecules that help in the expansion and activation of T cells are also under investigation. For instance, both interleukin (IL)-7 and IL-15 are γ-c signaling cytokines that substantially augment T-cell response to vaccination and have been shown to improve antitumor effects in animal models.87,88 Costimulatory molecules include 4-1BB ligands, OX40 ligands, and CD28 ligands, all of which can enhance T-cell expansion following activation. Anti-4-1BB antibodies have been shown to have potent antitumor effects in vivo. 

Finally, inhibition of regulatory pathways remains a major area of study because suppressive mediators released by tumors play a central role in limiting antitumor immunity. Among these are blocking antibodies to CTLA4, methods to depleted CD25 regulatory T cells, blockers of PD-1, and its ligand, PD-L1. The combination of these strategies that will ultimately be most promising in augmenting antitumor immunity remains to be seen.
 
IL-2 is active against renal cell carcinoma and malignant melanoma; however, for pediatric tumors, several trials of IL-2 have been performed with no antitumor effects observed.89,90,91 Even in neuroblastoma, a potentially immunoresponsive solid tumor,92,93,94 systemic administration of IL-2 as a single agent has shown no benefit.90 Moreover, recent studies have clearly demonstrated that, in addition to activating natural killer cells (the presumed mechanism responsible for the antitumor effects), IL-2 also substantially expands and activates CD25+ CD4+ regulatory T cells.95 This subset is a significant mediator of tumor-induced immune suppression; therefore, the administration of IL-2 in the context of cancer is likely to amplify this already suppressive subset.
 
Few other cytokines have been administered as single agents in children with cancer. Interferon (IFN)-α is probably the most well-studied cytokine and has been documented in the treatment of patients with chronic myelogenous leukemia (CML), hairy cell leukemia, some B-cell and T-cell lymphomas, and solid tumors, such as melanoma, renal carcinoma, and Kaposi sarcoma, all of which are very rare in pediatric patients. IFN-α is approved by the US Food and Drug Administration (FDA) for the adjuvant therapy of adults with stage III melanoma. An ongoing clinical trial is examining the use of IFN-α in children with melanoma.96 Ongoing phase I trials are also exploring the role of pegylated IFN-α for plexiform neurofibromas and brain tumors in children (see Clinicaltrials.gov). How IFN-α mediates antitumor effects remains unclear. Regional therapy with TNF-α has been performed in patients with sarcoma, and some antitumor responses were observed in Ewing sarcoma and Wilms tumor, although this approach is limited by the development of systemic toxicity.97
 
Recombinant GM-CSF (sargramostim) is a growth factor that may act on cancer cells through a role in cytokine priming. When given before and during induction chemotherapy, recombinant GM-CSF may make leukemic blast cells more susceptible to the cytotoxic effects of chemotherapy. This growth factor causes upregulation of costimulatory molecule expression on leukemia blasts in vitro and, in combination with INF-α, can induce antitumor immune responses in relapsed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) after allogeneic stem cell transplantation.98

Tumor cells engineered to secrete GM-CSF are particularly effective as antitumor vaccines, and the addition of GM-CSF to standard vaccines may increase their effectiveness by recruiting dendritic cells (DCs) to the site of vaccination.99 GM-CSF is also commonly administered locally at the site of administration of tumor vaccines, where it presumably enhances antigen presentation via recruitment of antigen presenting cells to the site where the immunogen is deposited. A novel application of inhaled GM-CSF may be for children with pulmonary metastases from sarcomas, with one child with Ewing sarcoma demonstrating a complete response.100,101 Of 40 patients treated with pulmonary metastases, 24 had disease stabilization or partial regression for a mean duration of 10 months.101 This included 8 of 13 patients with sarcoma who responded.

Monoclonal Antibodies

When Kohler and Milstein reported the technology for generating monoclonal antibodies (MABs) in 1975, many tumor biologists expected the rapid evolution of various antibodies that could act as “magic bullets” to target and kill tumors.102  Although progress in the field of MAB therapy for neoplasia has proceeded much slower than was initially anticipated, recent clinical trials have demonstrated antitumor activity in various malignancies.
 
Effective MAB therapy for cancer requires the identification of appropriate tumor-specific targets expressed on the surface of the cancer cells. For effective targeting, the molecule should be relatively tumor-specific (eg, show substantially less binding to normal tissues or binding to only “dispensable tissue” (eg, B cells). It should be highly expressed in tumors (compared with normal tissues), and the target of the MAB should not be shed from the tumor following MAB binding, rather the antigen-MAB complex should be internalized by the tumor cell. Importantly, many antigens are downregulated following antibody binding, which can limit the effectiveness of the therapy.
 
In addition, MABs are theoretically “foreign proteins” and, therefore, could induce an immune response that could limit their efficacy. Thus, MABs must be sufficiently rendered nonimmunogenic to prevent development of neutralizing antibodies. MABs were initially produced by fusing murine myeloma cells with B cells from mice immunized with specific antigens. Because MABs generated in this manner are murine proteins, they are recognized as foreign in immunocompetent humans and, thus, generate neutralizing antimurine antibodies termed human antimouse antibodies (HAMAs). 

Following development of these antibodies in patients, the half-life of MABs is greatly reduced, which significantly reduces their biologic activity. Advances in genetic engineering subsequently allowed the creation of chimeric antibodies, which use human constant regions and retain the entire murine variable region, and humanized antibodies, which retain only the murine hypervariable region responsible for epitope binding. The rest of the variable region and the entire constant region are human derived. More recently, fully human MABs have become readily available and further limit the likelihood of neutralizing antibody development.
 
The overall success of MAB therapy in cancer is determined by the ability for antibody binding to result in tumor cell death. This can occur via 1 of 3 pathways, which are not mutually exclusive. This includes the following:
 

  • Immune effects through antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis: Binding the antibody recruits cells with Fc receptors to the site of the tumor, which then kill the tumor cell, and/or complement is fixed and the tumor cell is killed.
  • Direct killing
    • Interruption of a critical cell signaling cascade by inhibition of ligand binding
    • Downregulation of a receptor tyrosine kinase, which transmits a necessary life signal
    • Induction of an apoptotic signal following ligation of the target by the MAB
  • Targeting via a conjugated antibody of antibody receptor (eg, radionuclide, immunotoxin, cell-based genetic fusion) that targets a lethal “hit” to the tumor cell

Ongoing work in this field is focused on identifying approaches to increase ADCC using agents such as GM-CSF to improve recruitment of effector cells in combination with an MAB for refractory osteosarcoma and neuroblastoma.103,104,105 Indeed, differences in the relative potency of ADCC effects with differing antibodies106 and with genetic variation appears to be a primary determining factor in whether MAB therapy for cancer is effective.28
 
ADCC appears to be the primary mechanism of action for MABs targeting the GD2 disialoganglioside in neuroblastoma. Several studies have shown that neuroblastoma is susceptible to ADCC via lymphocytes, neutrophils, and activated macrophages. GD2 is expressed at high densities on nearly all neuroblastoma cells, is not shed from the cell surface, and is restricted to neuroectodermal tissues, thus representing a potentially good target for MAB therapy. Several antibodies directed against GD2 on the surface of neuroblastoma cells have been developed for use in patients.
 
Initial studies using the 3F8, an anti-GD2 MAB, demonstrated that the primary adverse effects of therapy were limited to results of acute toxicity.107 Despite toxicity, 3F8 MAB can be administered in the outpatient setting with symptomatic management of the toxic effects. Results of initial nonrandomized clinical trials report a long-term disease-free survival rate in patients with stage IV neuroblastoma comparable to those of historical control subjects without MAB exposure.107 Interestingly, evidence suggests that low levels of HAMA and the development of non-neutralizing anti-idiotypic antibodies (antibodies directed to the variable region of the immunizing antibody rather than to the constant region, which is the target of most HAMA) correlate with improved survival rates following adjuvant 3F8 MAB therapy.108 Trials using another anti-GD2 MAB, hu14.18, linked with either interleukin (IL)-2 or GM-CSF, also had toxicity that was reversible, but no clinicalresponsesweredocumented.109,104
 
MAB therapy may also effectively kill tumors when the MAB induces death in tumor cells following antibody binding. Examples of this approach include herceptin in HER2 that expresses breast carcinoma cells110 and anti-CD99 in Ewing sarcoma111,112 Unfortunately, CD99 is also expressed on hematopoietic progenitors and T cells, thus limiting its clinical potential for tumor targeting. In pediatric studies, MABs targeting vascular endothelial growth factor (VEGF) as well as the immunoglobulin (Ig)F-1 receptor have shown progress in preliminary reports, presumably via interruption of signaling pathways critical for tumor survival.113,114
 
Nonconjugated antibodies can also induce cell death if they crosslink a cell surface receptor that can initiate a downstream death cascade. Antibodies to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors show significant activity in vitro in pediatric tumors by initiating such a death pathway.115 Antibodies to CD40 can induce similar effects in melanoma and some carcinomas.116,117
 
Recent evidence has suggested that the capacity to induce cell death as a result of MAB binding can be synergistic with cytotoxic chemotherapy. Whether this synergism results from enhanced ADCC, from enhanced effects of an interrupted growth signal, or from both is not clear in every case. One example of this is trastuzumab, which targets the HER2 or NEU protooncogene in breast cancer and has substantially increased the chemotherapy response rate in various clinical trials.118 Based on the association of HER2 expression and worse survival in osteosarcoma,119 this antibody has recently been used in conjunction with standard chemotherapy for HER2 -positive osteosarcoma. However, one concern with this approach is that the HER2 expression in osteosarcoma does not result from gene amplification as it does in breast carcinoma; therefore, interrupting HER2 signaling is not likely to result in death in this tumor. 
 
A third mechanism by which antibodies can kill tumor cells involves targeted delivery of a lethal agent, such as a toxin or radionuclide. With rituximab, an unconjugated MAB against CD20, a 96% overall response rate was reported in one phase II trial for lymphocyte-predominant Hodgkin lymphoma, with 75% remaining in remission after one year.120 Another phase II trial showed similar results.121  A phase II pilot study is underway through the Children’s Oncology Group to assess the toxicity of adding rituximab to upfront chemotherapy for B-cell leukemia and lymphoma (see Clinicaltrials.gov). 

Conjugating anti-CD20 to radionuclides has shown success in children with Hodgkin lymphoma, although the bone marrow toxicity is substantial; therefore, this approach is generally undertaken in the setting of marrow rescue.122 Other MABs that have been conjugated to toxins in pediatric oncology have included conjugating ricin with anti-CD25 or CD30 for Hodgkin lymphoma123,124 and pseudomonal exotoxin with anti-CD22 for ALL.125
 
In pediatric AML, the differentiation antigen CD33 is expressed in almost all patients. The FDA has approved anti-CD33 conjugated to calicheamicin (Mylotarg) for the treatment of AML in adults. Apart from some infusional allergic reactions, the primary toxicity of this approach has been bone marrow suppression caused by binding the MAB-toxin conjugate to normal hematopoietic precursors that express CD33. Another still unexplained toxicity of anti-CD33–calicheamicin conjugates is hepatic damage, which is characterized by transient increases in liver enzymes in approximately 25% of patients and, occasionally, a more severe complication consistent with venoocclusive disease.126 Currently, the agent is being tested both as a single agent and in combination with chemotherapy in children with AML; however, results of phase I and II clinical trials indicate promise, with an overall remission response rate of 45% and a 1-year event-free survival and overall survival estimates of38%and 53%, respectively.127,128
 
Genetic engineering has recently opened serious prospects of using the cytolytic machinery of T cells or natural killer cells with the effective targeting properties of antibodies via creation of so-called chimeric antigen receptors (CARs). In this case, a single-chain Fv-Fc fragment of an MAB is fused to the signaling chain of the T-cell receptor and is introduced genetically into T cells or natural killer cells. The cells are then systemically delivered or delivered at the site of the tumor; following engagement of the chimeric receptor with its target, T-cell activation or natural killer cell activation leads to tumor cytolysis. Promising preclinical results have been recently reported using direct administration of such T cells expressing CARs in a murine model of medulloblastoma.129

Overview of Current Immunotherapies

  • Innate immunity
    • Innate immunity does not induce immunologic memory.
    • Innate immunity can directly kill tumor cells.
    • This immunity plays a critical role in initiating adaptive immune responses
    • Innate immunity includes the role of toll-like receptors (TLRs) in improving antitumor and vaccine responses, muramyl tripeptide phosphatidylethanolamine (MTP-PE) in osteosarcoma, and natural killer cell–killer immunoglobulinlike receptor mismatch.
    • This can also augment tumor growth and invasion.
  • Adaptive immunity
    • Induces immunologic memory and can directly kill tumor cells or recruit other effectors through cytokine production.
    • T cells are potent tumor cell killers that recognize peptides derived from the target cell (extracellular or intracellular) but must be presented by major histocompatibility complex (MHC) molecules.
    • Activation of T cells also requires a second signal provided by a costimulatory molecule.
    • T cells used in a donor lymphocyte infusion or as part of a stem cell transplant can have potent graft-versus-leukemia effects.
    • Vaccines have been designed as a means of providing a targeted tumor antigen with an appropriate costimulatory signal to enhance T-cell responses.
    • Cytokines and growth factors have been used on pediatric tumors as a means of directly killing tumors or improving host antitumor responses but with limited success.
    • B cells are professional antigen-presenting cells (APCs) that generate antibodies in response to a foreign antigen.
    • Monoclonal antibodies (MABs) target only cell surface antigens and can induce antibody-dependent cellular cytotoxicity (ADCC) or complement fixation; they can be directly cytotoxic or serve as targeting agents to deliver lethal “hits.”
    • MABs have been used as single agents or in combination with chemotherapy and can be conjugated with radioisotopes or toxins to enhance their potency.

Keywords

immunotherapeutic targeting, pediatric oncology, immunology, innate immune system, Coley toxins, toll-like receptor, TLR, antigen presenting cell, APC, acute myeloid leukemia, AML, dendritic cells, DC, high mobility group box protein 1, HMGB1, muramyl tripeptide phosphatidylethanolamine, MTP-PE, interleukin, IL, tumor necrosis factor, TNF, natural killer cell, NK cell, killer immunoglobulin-like receptors, KIR, major histocompatibility complex, MHC, adaptive immune system, bone marrow transplantation, BMT, donor leukocyte infusions, DLI, chronic myelogenous leukemia, CML, graft versus leukemia effect, GVL, graft versus host disease, GVHD

acute lymphoblastic leukemia, ALL, histocompatibility leukocyte antigen, HLA, cytokines, growth factors, granulocyte-macrophage colony-stimulating factor, GM-CSF, interferon, IFN, monoclonal antibodies, MAB; human antimouse antibodies, HAMA, antibody-dependent cellular cytotoxicity, ADCC, chimeric antigen receptor, CAR, sarcomas, Ewing sarcoma, lymphoma, neuroblastoma, rhabdomyosarcoma, human papilloma virus, osteosarcoma, lung cancer

 


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References
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References

  1. Giavazzi R, Bucana CD, Hart IR. Correlation of tumor growth inhibitory activity of macrophages exposed to adriamycin and adriamycin sensitivity of the target tumor cells. J Natl Cancer Inst. Aug 1984;73(2):447-55. [Medline].

  2. Kleinerman ES. Biologic therapy for osteosarcoma using liposome-encapsulated muramyl tripeptide. Hematol Oncol Clin North Am. Aug 1995;9(4):927-38. [Medline].

  3. Kleinerman ES, Gano JB, Johnston DA, Benjamin RS, Jaffe N. Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol. Apr 1995;18(2):93-9. [Medline].

  4. Kontny HU, Lehrnbecher TM, Chanock SJ, Mackall CL. Simultaneous expression of Fas and nonfunctional Fas ligand in Ewing's sarcoma. Cancer Res. Dec 15 1998;58(24):5842-9. [Medline].

  5. Shtil AA, Turner JG, Dalton WS, Yu H. Alternative pathways of cell death to circumvent pleiotropic resistance in myeloma cells: role of cytotoxic T-lymphocytes. Leuk Lymphoma. Jun 2000;38(1-2):59-70. [Medline].

  6. Cullen KV, Davey RA, Davey MW. Drug resistance does not correlate with resistance to Fas-mediated apoptosis. Leuk Res. Jan 2001;25(1):69-75. [Medline].

  7. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-60. [Medline].

  8. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. Jan 2006;6(1):24-37. [Medline].

  9. Merchant MS, Melchionda F, Sinha M, Khanna C, Helman L, Mackall CL. Immune reconstitution prevents metastatic recurrence of murine osteosarcoma. Cancer Immunol Immunother. Jul 2007;56(7):1037-46. [Medline].

  10. Coley WB. Late results of the treatment of inoperable sarcoma by the mixed toxins and erysipelas and Bacillus prodigiosus. Am J Med Sci. 1906;131:373.

  11. Hall SS. A Commotion in the Blood. ed. New York, NY: Henry Holt & Co; 1997.

  12. See HC, Swift WE, Coley BL. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley. Research Cancer. 1946;6:205-16.

  13. Ghiringhelli F, Apetoh L, Housseau F, Kroemer G, Zitvogel L. Links between innate and cognate tumor immunity. Curr Opin Immunol. Apr 2007;19(2):224-31. [Medline].

  14. Roses RE, Xu M, Koski GK, Czerniecki BJ. Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer. Oncogene. Jan 7 2008;27(2):200-7. [Medline].

  15. Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene. Jan 7 2008;27(2):218-24. [Medline].

  16. Brandau S, Suttmann H. Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother. Jul 2007;61(6):299-305. [Medline].

  17. Kanzler H, Barrat FJ, Hessel EM, Coffman RL. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med. May 2007;13(5):552-9. [Medline].

  18. Weeratna R, Davis H, Medynski L, Kreig A. Potential use of CPG ODN for cancer immunotherapy. Update on Cancer Therapeutics. 2006;1:49-58.

  19. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. Jan 2008;8(1):59-73. [Medline].

  20. Paulos CM, Wrzesinski C, Kaiser A, et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest. Aug 2007;117(8):2197-204. [Medline].

  21. Tesniere A, Panaretakis T, Kepp O, et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. Jan 2008;15(1):3-12. [Medline].

  22. Ullrich E, Menard C, Flament C, et al. Dendritic cells and innate defense against tumor cells. Cytokine Growth Factor Rev. Feb 2008;19(1):79-92. [Medline].

  23. Riuzzi F, Sorci G, Donato R. RAGE expression in rhabdomyosarcoma cells results in myogenic differentiation and reduced proliferation, migration, invasiveness, and tumor growth. Am J Pathol. Sep 2007;171(3):947-61. [Medline].

  24. Mori K, Ando K, Heymann D. Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases. Expert Rev Anticancer Ther. Feb 2008;8(2):151-9. [Medline].

  25. Nardin A, Lefebvre ML, Labroquere K, et al. Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Curr Cancer Drug Targets. Mar 2006;6(2):123-33. [Medline].

  26. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. May 2008;9(5):495-502. [Medline].

  27. Ruggeri L, Mancusi A, Burchielli E, Aversa F, Martelli MF, Velardi A. Natural killer cell alloreactivity in allogeneic hematopoietic transplantation. Curr Opin Oncol. Mar 2007;19(2):142-7. [Medline].

  28. Kim DH, Jung HD, Kim JG, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. Oct 15 2006;108(8):2720-5. [Medline].

  29. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The central role of CD4(+) T cells in the antitumor immune response. J Exp Med. Dec 21 1998;188(12):2357-68. [Medline].

  30. Kleinerman ES, Erickson KL, Schroit AJ, et al. Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res. May 1983;43(5):2010-4. [Medline].

  31. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. Sep 2006;25(3):315-22. [Medline].

  32. Vakkila J, Jaffe R, Michelow M, Lotze MT. Pediatric cancers are infiltrated predominantly by macrophages and contain a paucity of dendritic cells: a major nosologic difference with adult tumors. Clin Cancer Res. Apr 1 2006;12(7 Pt 1):2049-54. [Medline].

  33. Berzofsky JA, Terabe M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J Immunol. Mar 15 2008;180(6):3627-35. [Medline].

  34. Cui J, Shin T, Kawano T, et al. Requirement of V{alpha}14NKT cells in IL-12-mediated rejection of tumors. Science. 1997;278:1623-1626. [Medline].

  35. Smyth MJ, Thia KY, Street SE, et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. Feb 21 2000;191(4):661-8. [Medline].

  36. Crowe NY, Smyth MJ, Godfrey DI. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J Exp Med. Jul 1 2002;196(1):119-27. [Medline].

  37. Ishikawa A, Motohashi S, Ishikawa E, et al. A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. Mar 1 2005;11(5):1910-7. [Medline].

  38. Motohashi S, Ishikawa A, Ishikawa E, et al. A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. Oct 15 2006;12(20 Pt 1):6079-86. [Medline].

  39. Talmadge JE. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res. Sep 15 2007;13(18 Pt 1):5243-8. [Medline].

  40. Sanders JE, Flournoy N, Thomas ED, et al. Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graft-versus-host disease. Med Pediatr Oncol. 1985;13(4):165-72. [Medline].

  41. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. Feb 1 1990;75(3):555-62. [Medline].

  42. Bacigalupo A, Van Lint MT, Occhini D, et al. Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood. Apr 1 1991;77(7):1423-8. [Medline].

  43. Rassam SM, Katz F, Chessells JM, Morgan G. Successful allogeneic bone marrow transplantation in juvenile CML: conditioning or graft-versus-leukaemia effect?. Bone Marrow Transplant. Mar 1993;11(3):247-50. [Medline].

  44. Passweg JR, Tiberghien P, Cahn JY, et al. Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant. Jan 1998;21(2):153-8. [Medline].

  45. Locatelli F, Zecca M, Rondelli R, et al. Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA- identical sibling bone marrow transplantation: results of a randomized trial. Blood. Mar 1 2000;95(5):1572-9. [Medline].

  46. Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. May 1 1989;73(6):1720-8. [Medline].

  47. Maraninchi D, Gluckman E, Blaise D, et al. Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet. Jul 25 1987;2(8552):175-8. [Medline].

  48. Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood. Dec 1 2001;98(12):3192-204. [Medline].

  49. Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. Sep 15 2002;100(6):1997-2004. [Medline].

  50. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood. Sep 1 1995;86(5):2041-50. [Medline].

  51. Atra A, Millar B, Shepherd V, et al. Donor lymphocyte infusion for childhood acute lymphoblastic leukaemia relapsing after bone marrow transplantation. Br J Haematol. Apr 1997;97(1):165-8. [Medline].

  52. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. Feb 1997;15(2):433-44. [Medline].

  53. Singhal S, Powles R, Kulkarni S, et al. Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse. Leuk Lymphoma. Feb 1999;32(5-6):505-12. [Medline].

  54. Cross NC, Hughes TP, Feng L, et al. Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: correlations with acute graft-versus-host disease and relapse. Br J Haematol. May 1993;84(1):67-74. [Medline].

  55. Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant. Mar 2008;41(5):483-93. [Medline].

  56. Champlin R, Khouri I, Kornblau S, et al. Allogeneic hematopoietic transplantation as adoptive immunotherapy. Induction of graft-versus-malignancy as primary therapy. Hematol Oncol Clin North Am. Oct 1999;13(5):1041-57, vii-viii. [Medline].

  57. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. Sep 14 2000;343(11):750-8. [Medline].

  58. Meunier MC, Delisle JS, Bergeron J, Rineau V, Baron C, Perreault C. T cells targeted against a single minor histocompatibility antigen can cure solid tumors. Nat Med. Nov 2005;11(11):1222-9. [Medline].

  59. Burdach S, van Kaick B, Laws HJ, et al. Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol. Nov 2000;11(11):1451-62. [Medline].

  60. Geiger JD, Hutchinson RJ, Hohenkirk LF, et al. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res. Dec 1 2001;61(23):8513-9. [Medline].

  61. Koscielniak E, Gross-Wieltsch U, Treuner J, et al. Graft-versus-Ewing sarcoma effect and long-term remission induced by haploidentical stem-cell transplantation in a patient with relapse of metastatic disease. J Clin Oncol. Jan 1 2005;23(1):242-4. [Medline].

  62. Lang P, Pfeiffer M, Muller I, et al. Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. Klin Padiatr. Nov-Dec 2006;218(6):321-6. [Medline].

  63. Miano M, Labopin M, Hartmann O, et al. Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. Jan 2007;39(2):89-99. [Medline].

  64. Satwani P, Cooper N, Rao K, Veys P, Amrolia P. Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases. Bone Marrow Transplant. Jan 2008;41(2):173-82. [Medline].

  65. Rosenberg SA, White DE. Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy. J Immunother Emphasis Tumor Immunol. Jan 1996;19(1):81-4. [Medline].

  66. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. Sep 2004;10(9):909-15. [Medline].

  67. Brichard VG, Lejeune D. Cancer immunotherapy targeting tumour-specific antigens: towards a new therapy for minimal residual disease. Expert Opin Biol Ther. Jul 2008;8(7):951-68. [Medline].

  68. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. Jul 1 2006;24(19):3089-94. [Medline].

  69. Alanko S, Salmi TT, Pelliniemi TT. Recovery of blood T-cell subsets after chemotherapy for childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. May-Jun 1994;11(3):281-92. [Medline].

  70. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med. Jan 19 1995;332(3):143-9. [Medline].

  71. Mackall CL, Gress RE. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev. Jun 1997;157:61-72. [Medline].

  72. Mackall CL, Hakim FT, Gress RE. Restoration of T-cell homeostasis after T-cell depletion. Semin Immunol. Dec 1997;9(6):339-46. [Medline].

  73. Mackall CL, Rhee EH, Read EJ, et al. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res. Aug 1 2008;14(15):4850-8. [Medline].

  74. Mackall CL, Stein D, Fleisher TA, et al. Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults. Blood. Jul 15 2000;96(2):754-62. [Medline].

  75. Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. Aug 2006;120(2):121-8. [Medline].

  76. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. Apr 2008;8(4):299-308. [Medline].

  77. Sarkar AK, Nuchtern JG. Lysis of MYCN-amplified neuroblastoma cells by MYCN peptide-specific cytotoxic T lymphocytes. Cancer Res. Apr 1 2000;60(7):1908-13. [Medline].

  78. Dagher R, Long LM, Read EJ, et al. Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study. Med Pediatr Oncol. Mar 2002;38(3):158-64. [Medline].

  79. Oka Y, Tsuboi A, Elisseeva OA, et al. WT1 peptide cancer vaccine for patients with hematopoietic malignancies and solid cancers. ScientificWorldJournal. 2007;7:649-65. [Medline].

  80. Rezvani K, Yong AS, Savani BN, et al. Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia. Blood. Sep 15 2007;110(6):1924-32. [Medline].

  81. Geiger J, Hutchinson R, Hohenkirk L, McKenna E, Chang A, Mule J. Treatment of solid tumours in children with tumour-lysate-pulsed dendritic cells. Lancet. Sep 30 2000;356(9236):1163-5. [Medline].

  82. Brenner M. Phase I study of cytokine-gene modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma. Human gene therapy. 1992;3:665-76.

  83. Brenner MK, Heslop H, Krance R, et al. Phase I study of chemokine and cytokine gene-modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma using an adenoviral vector. Hum Gene Ther. Jul 1 2000;11(10):1477-88. [Medline].

  84. Bowman L, Grossmann M, Rill D, et al. IL-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma. Blood. Sep 15 1998;92(6):1941-9. [Medline].

  85. Rousseau RF, Haight AE, Hirschmann-Jax C, et al. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood. Mar 1 2003;101(5):1718-26. [Medline].

  86. Russell HV, Strother D, Mei Z, et al. Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J Immunother. Feb-Mar 2007;30(2):227-33. [Medline].

  87. Melchionda F, Fry TJ, Milliron MJ, McKirdy MA, Tagaya Y, Mackall CL. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool. J Clin Invest. May 2005;115(5):1177-87. [Medline].

  88. Oh S, Perera LP, Terabe M, Ni L, Waldmann TA, Berzofsky JA. IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis. Proc Natl Acad Sci U S A. Apr 1 2008;105(13):5201-6. [Medline].

  89. Roper M, Smith MA, Sondel PM, et al. A phase I study of interleukin-2 in children with cancer. Am J Pediatr Hematol Oncol. Nov 1992;14(4):305-11. [Medline].

  90. Bauer M, Reaman GH, Hank JA, et al. A phase II trial of human recombinant interleukin-2 administered as a 4-day continuous infusion for children with refractory neuroblastoma, non-Hodgkins lymphoma, sarcoma, renal cell carcinoma, and malignant melanoma. A Childrens Cancer Group study. Cancer. Jun 15 1995;75(12):2959-65. [Medline].

  91. Kalwak K, Ussowicz M, Gorczynska E, et al. Immunologic effects of intermediate-dose IL-2 i.v. after autologous hematopoietic cell transplantation in pediatric solid tumors. J Interferon Cytokine Res. Apr 2003;23(4):173-81. [Medline].

  92. Castriconi R, Dondero A, Cilli M, et al. Human NK cell infusions prolong survival of metastatic human neuroblastoma-bearing NOD/scid mice. Cancer Immunol Immunother. Nov 2007;56(11):1733-42. [Medline].

  93. Joshi AD, Clark EM, Wang P, et al. Immunotherapy of human neuroblastoma using umbilical cord blood-derived effector cells. J Neuroimmune Pharmacol. Jun 2007;2(2):202-12. [Medline].

  94. Verneris MR, Wagner JE. Recent developments in cell-based immune therapy for neuroblastoma. J Neuroimmune Pharmacol. Jun 2007;2(2):134-9. [Medline].

  95. Zhang H, Chua KS, Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med. Nov 2005;11(11):1238-43. [Medline].

  96. Navid F, Furman WL, Fleming M, et al. The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma. Cancer. Feb 15 2005;103(4):780-7. [Medline].

  97. Seibel NL, Dinndorf PA, Bauer M, Sondel PM, Hammond GD, Reaman GH. Phase I study of tumor necrosis factor-alpha and actinomycin D in pediatric patients with cancer: a Children's Cancer Group study. J Immunother Emphasis Tumor Immunol. Aug 1994;16(2):125-31. [Medline].

  98. Arellano ML, Langston A, Winton E, Flowers CR, Waller EK. Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant. Jan 2007;13(1):116-23. [Medline].

  99. Zhang WG, Liu SH, Cao XM, et al. A phase-I clinical trial of active immunotherapy for acute leukemia using inactivated autologous leukemia cells mixed with IL-2, GM-CSF, and IL-6. Leuk Res. Jan 2005;29(1):3-9. [Medline].

  100. Anderson PM, Markovic SN, Sloan JA, et al. Aerosol granulocyte macrophage-colony stimulating factor: a low toxicity, lung-specific biological therapy in patients with lung metastases. Clin Cancer Res. Sep 1999;5(9):2316-23. [Medline].

  101. Rao RD, Anderson PM, Arndt CA, Wettstein PJ, Markovic SN. Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol. Oct 2003;26(5):493-8. [Medline].

  102. Kohler G, Milstein C. Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion. Eur J Immunol. Jul 1976;6(7):511-9. [Medline].

  103. Yu AL, Uttenreuther-Fischer MM, Huang CS, et al. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol. Jun 1998;16(6):2169-80. [Medline].

  104. Ozkaynak MF, Sondel PM, Krailo MD, et al. Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children's Cancer Group Study. J Clin Oncol. Dec 15 2000;18(24):4077-85. [Medline].

  105. Kushner BH, Kramer K, Cheung NK. Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol. Nov 15 2001;19(22):4189-94. [Medline].

  106. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. Apr 2000;6(4):443-6. [Medline].

  107. Cheung NK. Monoclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep. Nov 2000;2(6):547-53. [Medline].

  108. Cheung NK, Guo HF, Heller G, Cheung IY. Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma. Clin Cancer Res. Jul 2000;6(7):2653-60. [Medline].

  109. Osenga KL, Hank JA, Albertini MR, et al. A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group. Clin Cancer Res. Mar 15 2006;12(6):1750-9. [Medline].

  110. Wilson WH. Chemotherapy sensitization by rituximab: experimental and clinical evidence. Semin Oncol. Dec 2000;27(6 Suppl 12):30-6. [Medline].

  111. Scotlandi K, Baldini N, Cerisano V, et al. CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res. Sep 15 2000;60(18):5134-42. [Medline].

  112. Scotlandi K, Perdichizzi S, Bernard G, et al. Targeting CD99 in association with doxorubicin: an effective combined treatment for Ewing's sarcoma. Eur J Cancer. Jan 2006;42(1):91-6. [Medline].

  113. Bender JL, Adamson PC, Reid JM, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children's Oncology Group Study. J Clin Oncol. Jan 20 2008;26(3):399-405. [Medline].

  114. Benesch M, Windelberg M, Sauseng W, et al. Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors. Ann Oncol. Apr 2008;19(4):807-13. [Medline].

  115. Merchant MS, Yang X, Melchionda F, et al. Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing's sarcoma. Cancer Res. Nov 15 2004;64(22):8349-56. [Medline].

  116. Loskog A, Totterman TH. CD40L - a multipotent molecule for tumor therapy. Endocr Metab Immune Disord Drug Targets. Mar 2007;7(1):23-8. [Medline].

  117. Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. Mar 1 2007;25(7):876-83. [Medline].

  118. Emens LA, Reilly RT, Jaffee EM. Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity. Endocr Relat Cancer. Mar 2005;12(1):1-17. [Medline].

  119. Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol. Sep 1999;17(9):2781-8. [Medline].

  120. Rehwald U, Schulz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. Jan 15 2003;101(2):420-4. [Medline].

  121. Ekstrand BC, Lucas JB, Horwitz SM, et al. Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial. Blood. Jun 1 2003;101(11):4285-9. [Medline].

  122. Cooney-Qualter E, Krailo M, Angiolillo A, et al. A phase I study of 90yttrium-ibritumomab-tiuxetan in children and adolescents with relapsed/refractory CD20-positive non-Hodgkin's lymphoma: a Children's Oncology Group study. Clin Cancer Res. Sep 15 2007;13(18 Pt 2):5652s-5660s. [Medline].

  123. Schnell R, Borchmann P, Staak JO, et al. Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin's lymphoma. Ann Oncol. May 2003;14(5):729-36. [Medline].

  124. Schnell R, Staak O, Borchmann P, et al. A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma. Clin Cancer Res. Jun 2002;8(6):1779-86. [Medline].

  125. Wayne AS, Kreitman RJ, Pastan I. Monoclonal antibodies and immunotoxins... In: American Society of Clinical Oncology 2007 Educational Book. Alexandria, VA: 2007:596-601.

  126. Giles FJ, Kantarjian HM, Kornblau SM, et al. Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer. Jul 15 2001;92(2):406-13. [Medline].

  127. Aplenc R, Alonzo TA, Gerbing RB, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol. May 10 2008;26(14):2390-3295. [Medline].

  128. Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood. Aug 15 2005;106(4):1183-8. [Medline].

  129. Ahmed N, Ratnayake M, Savoldo B, et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. Jun 15 2007;67(12):5957-64. [Medline].

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Further Reading

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Keywords

immunotherapeutic targeting, pediatric oncology, immunology, innate immune system, Coley toxins, toll-like receptor, TLR, antigen presenting cell, APC, acute myeloid leukemia, AML, dendritic cells, DC, high mobility group box protein 1, HMGB1, muramyl tripeptide phosphatidylethanolamine, MTP-PE, interleukin, IL, tumor necrosis factor, TNF, natural killer cell, NK cell, killer immunoglobulin-like receptors, KIR, major histocompatibility complex, MHC, adaptive immune system, bone marrow transplantation, BMT, donor leukocyte infusions, DLI, chronic myelogenous leukemia, CML, graft versus leukemia effect, GVL, graft versus host disease, GVHD

acute lymphoblastic leukemia, ALL, histocompatibility leukocyte antigen, HLA, cytokines, growth factors, granulocyte-macrophage colony-stimulating factor, GM-CSF, interferon, IFN, monoclonal antibodies, MAB; human antimouse antibodies, HAMA, antibody-dependent cellular cytotoxicity, ADCC, chimeric antigen receptor, CAR, sarcomas, Ewing sarcoma, lymphoma, neuroblastoma, rhabdomyosarcoma, human papilloma virus, osteosarcoma, lung cancer

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Contributor Information and Disclosures

Author

Crystal L Mackall, MD, Deputy Branch Chief, Head of Immunology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health
Crystal L Mackall, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Immunologists, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Christian M Capitini, MD, Clinical Fellow in Pediatric Hematology/Oncology, National Cancer Institute and Johns Hopkins Hospital
Christian M Capitini, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Medical Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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