How Neuroblastoma Escapes the Innate and Adaptive Immune Systems

Neuroblastoma employs a variety of tactics to evade the immune system (Table 14.2). It downregulates immune-activating while overexpressing immune-inhibitory receptors. By repressing the expression of class-I and class-II MHC (Lampson et al. 1983) as well as CD1d (Metelitsa et al. 2001), they interfere with both the afferent and efferent arms of adaptive immune response. In addition, NB cells can avoid immune recognition and destruction by releas Table 14.2. Neuroblastoma can evade the immune...

Conclusion

High-risk neuroblastoma presents a continuing therapeutic challenge. Progress thus far in combination chemotherapy, local control, myeloablative consolidation therapy, and treatment with differentiating agents for microscopic residual disease has improved the overall prognosis. Although the 3-year event-free survival for children with stage-4 disease has improved from < 10 to > 40 in the past two decades, late relapses continue to be a challenge such that the overall cure rate for stage-4...

Demethylating Agents

Caspase-8 expression acts as a key determinant of sensitivity for apoptosis induced by death-inducing lig-ands or cytotoxic drugs. Caspase 8 has been shown to be preferentially silenced in neuroblastoma (Teitz et al. 2000). In tumor cell lines resistant to TRAIL, anti-CD95 or TNF-alpha, caspase-8 protein and mRNA expression was decreased or absent without caspase-8 gene loss. Methylation-specific PCR revealed hypermethylation of caspase-8 regulatory sequences in cells with impaired caspase-8...

Frequent Symptoms

Presenting signs and symptoms of children with neu-roblastoma reflect both the location of the primary tumor and the extent of disease. The typical patient with neuroblastoma is an infant or a toddler. Pain from abdominal distension or metastases to bone is common (30 ). Many patients fail to gain weight or have weight loss (11 ). The characteristic bilater al periorbital ecchymosis, which is a sign of meta-static disease, is typically caused by intraorbital masses. In contrast, infants with...

Endocrine 18321 Thyroid Function

Primary hypothyroidism is a common late effect observed in cancer survivors who received head and neck radiation (Kaplan et al. 1983 Halperin et al. 1999). The occurrence of thyroid dysfunction is related, primarily, to the dose of radiotherapy administered but is also influenced by the age and gender of the patient and the time elapsed since the end of treatment (Sklar et al. 2000). A higher incidence of clinically significant hy-pothyroidism is observed above radiation doses of 2000 cGy...

Effector Mechanisms of MAb

Anti-tumor MAb can carry out highly effective tu-moricidal functions both in vitro and in vivo these include signaling through receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-mediated cytotoxicity (CMC) (Cheung 2004). MAb vary in their ability to induce downstream effects. For example, MAb 3F8 is unique among anti-GD2 antibodies in its ability to induce apoptosis among EL4 murine lymphoma cells (Tom-linson et al., unpublished results). MAb can also block...

Cd55

Inhibition of immune cells Lymphocytes APC * N.K.Cheung and W.Gerald, microarray gene expression analysis of human NB, unpublished results LMP low molecular weight protein, TAP transporter-associated protein * N.K.Cheung and W.Gerald, microarray gene expression analysis of human NB, unpublished results LMP low molecular weight protein, TAP transporter-associated protein ing the ganglioside GD1a which is directly toxic to human lymphocytes while uncoupling cell signaling through the NFkB pathway...

References

Antunes NL (2000) Acute neurologic complications in children with systemic cancer. J Child Neurol 15 705-716 Antunes NL, Khakoo Y, Matthay KK et al. (2000) Antineuronal antibodies in patients with neuroblastoma and paraneo-plastic opsoclonus-myoclonus. J Pediatr Hematol Oncol 22 315-320 Banerjee S, Marwaha RK, Bajwa RPS (1995) Primary pelvic neuroblastoma with central nervous system metastases. Pediatr Hematol Oncol 12 309-312 Bataller L, Rosenfeld MR, Graus F et al. (2003) Autoantigen...

Info

Drotar D (ed) Measuring health-related quality of life in children and adolescents implications for research and practice. Lawrence Erlbaum Associates, Publishers, Mahwah, New Jersey Estilo CL, Huryn JM, Kraus DH et al. (2003) Effects of therapy on dentofacial development in long-term survivors of head and neck rhabdomyosarcoma the Memorial Sloan-Ketter-ing Cancer Center Experience. J Pediatr Hematol Oncol 25 215-222 Fulda S, Fichtner I, Hero B et al. (2001) Preclinical and clinical aspects on...

Phox2b

Regulation of transcription, DNA dependent, neurogenesis, development tive to non-neoplastic tissues (including fetal and mature brain tissue, spinal cord, bone marrow, liver, lung, and kidney). Many of the functionally annotated genes that are highly over-expressed in high-risk NB are believed to play a role in cell growth, development, differentiation, and histogenesis (unpublished data). A significant number are specifically annotated as playing a role in neurogenesis (Table 9.1). It is also...

Reproductive Endocrine Function Ovarian Dysfunction

Both chemotherapy and radiation therapy can induce ovarian dysfunction, which can be either transient or permanent. In the pre-pubertal state, ovaries are more resistant to chemotherapy-induced damage than in the post-pubertal individual (Rivkees and Crawford 1988 Halperin et al. 1999). Among all the chemotherapeutic agents, alkylating agents, including cyclophosphamide, ifosfamide, busulfan, BCNU, and CCNU, have most consistently caused ovarian damage. High doses of these agents are very toxic...

Treatment Related Neurologic Complications

All multi-modality treatments for neuroblastoma can be complicated by a number of potential acute and chronic neurologic complications that may warrant immediate attention or long-term therapy these include metabolic abnormalities (Antunes 2000), CNS changes and peripheral neuropathies (Reddy and Witek 2003 Yu et al. 1998 Cheung et al. 2001), infectious complications resulting in brain abscesses, meningitis, or encephalitis (Tasdemiroglu and Patchell 1997), or vascular events as a consequence...

Conclusions

In vivo destruction of NB cells by T-cell recognition, antibody-facilitated recognition, or recognition via cells of the innate immune system have proven effective in pre-clinical murine models. Anti-tumor benefit is likely to be maximized when applied at the time of minimal tumor burden. Unfortunately,to achieve a minimal disease state, intensely immunosuppressive chemotherapy and radiotherapy are often required, which predictably compromise the patient's immune competence. As such,...

Topoisomerase Inhibitors

Topoisomerase-I and topoisomerase-II inhibitors were the next chemotherapy class to be investigated for treatment of relapsed and newly diagnosed neu-roblastoma. Etoposide, a topoisomerase-II inhibitor, as detailed above, has been incorporated into relapse and primary treatment regimens for the past two decades, and is quite effective incorporated into regimens for newly diagnosed neuroblastoma (see Chap. 11). Unfortunately, a significant proportion of cell lines obtained from patients after...

Ivig

Immunomodulation decreases infections Flu-like post-infusion symptoms potential blood product risks that can trigger relapses Low risk of allergic reaction to murine component long-term effects unknown May be appropriate for mild cases ease of administration well known drug profile Cushingoid side effects ineffective in many cases Immunosuppressant easy to use and well tolerated drug levels can be monitored Newer inhibitor of lymphocyte proliferation may be more effective than azathioprine...

Surgical Complications and Mortality

In high-risk patients, neuroblastomas tend to involve and or encase major vascular and neural structures in their sites of origin or surrounding nodal echelons. Major surgical complications following neuroblastoma resection are listed by organ system in Table 11.4.3 most serious among them are massive hemorrhage, major vascular injury, and respiratory failure requiring mechanical ventilation after major surgery. Cervical and upper mediastinal resections are often associated with a permanent...

Stem Cell Transplantation Stephan AGrupp 1161 Introduction

The role of autologous stem cell transplantation (ASCT) as consolidation therapy for malignancies has been debated, both in the pediatric as well as the adult setting. General design criteria include (a) a chemo-responsive tumor type, typically with a good initial response to induction therapy,but a poor long-term (i.e., 3- or 5-year) outcome (b) a conditioning (pre-transplant chemotherapy) regimen that may be dose-escalated safely past marrow tolerance (c) conditioning agents not utilized in...

Syngeneic Models

Syngeneic models of neuroblastoma, most frequently derived from the C1300 tumor, have been used to probe the role of immunotherapy. This tumor arose spontaneously in the spinal cord region of a strain-A mouse (Ishizu et al. 1994 Ziegler et al. 1997) and as a subcutaneous implant shows local invasion but rarely metastasizes. A variant of C-1300, TBJ, grows more rapidly and metastasizes extensively, and C-1300 cells inoculated into a subcutaneously translocated spleen gives rise to hepatic...

H2ax

Genetic heterogeneity of LOH regions (depicted by black capped bars) may explain the failure to find the neuroblastoma suppressor gene. In case of genetic heterogeneity, there could actually be at least two (B, C), if not more genes involved, and these might be separated many megabases from each other. Combining these LOH regions into a single consensus region (A) would inevitably initiate a gene search in a region that is unlikely to harbor the long-sought NSG According to this hypothesis,...

Rare but Characteristic Symptoms

Rare but characteristic symptoms of neuroblastoma are shown in Table 7.1. Transverse myelopathy can result from growth of a cervical, intrathoracic, or intraabdominal neuroblas-toma through neural foramina into the spinal canal. Approximately half of the patients with dumbbell lesions initially present with neurological symptoms (Katzenstein et al. 2001), but myelopathy may develop soon afterwards,e.g., during surgery thus,the degree of intraspinal tumor extension should be evaluated by MRI...

Techniques for Stem Cell Mobilization

Large increases in the number of circulating stem and progenitor cells occur during recovery from myelosuppressive chemotherapy, typically when the absolute neutrophil count (ANC) has reached 1000 pl and rapidly rising. The exact point of maximal stem cell mobilization is difficult to predict and highly patient dependent (see 11.6.3.4). Commonly, cyclophosphamide (a total dose of 4 g m2 over 2 days) has been used. Multiple-drug regimens as part of the primary treatment can also be used to...

Clinical Relevance of MRD

The ultimate utility of MRD detection is to determine the clinical significance of occult tumor cells in relations to patient relapse, survival, and even cure, using progression-free and overall survival as the clinical end points. Prognostic impact of MRD needs to factor in the genetic profile of the tumor. For example, NB patients with stage-4s disease are well known to have marrow disease, and yet they predictably have favorable outcome. This suggests that the presence of marrow disease may...

Stromadominant and Stromapoor

Tumor in this category is characterized by the presence of one or more macroscopic, usually hemor-rhagic neuroblastomatous nodule s stroma-poor component coexisting with ganglioneuroblastoma, intermixed stroma-rich component or with gang-lioneuroma stroma-dominant component Fig. 8.1h . On microscopic examination, there is typically abrupt demarcation pushing border or even fibrous pseudo-capsular formation between the neu-roblastomatous nodule s and the stroma-rich or stro-ma-dominant tumor...

Ganglioneuroblastoma Intermixed Schwannian Stromarich

The international classification has stipulated that tumors having prominent Schwannian stromal development occupying more than 50 of the tumor tissue are upgraded to this category. Tumor histology is consistent with a transition to the full differentiation maturation of ganglioneuroma see below , but the process is not complete, as evidenced by scattered residual microscopic foci where neuroblastic cells in various stages of differentiation as well as varying numbers of maturing ganglion cells...

Ntype Neuroblastic Cells

In vitro, the predominant neuroblastic N cells resemble sympathoadrenoblasts - immature neural neuroendocrine precursors, with small rounded cell bodies and neuritic processes that vary widely in number and length. Cells adhere poorly to the under lying substrate but adhere well to each other to form cell clumps pseudoganglia , achieving high saturation densities in culture Rettig et al. 1987 Biedler et al. 1997 Spengler et al. 1997 . Biochemically, they express proteins for synthesis, binding,...

Neuronal differentiation

Sympathetic neurons, suggesting the important role of MASH1 in sympathetic differentiation Guillemot et al. 1993 . MASH1 is transiently induced during neural development to promote neuronal cell differentiation however,high hASH1 expression persists in neuroblastoma tumors and cell lines Soderholm et al. 1999 Ichimiya et al. 2001 . Retinoic acid treatment decreases the expression of hASH1 and induces neu-rite extension Ichimiya et al. 2001 . hASH1 also directly represses the expression of...