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Wilms tumor

Somjai Kanjanapongkul Queen Sirikit National Institute of Health

Wilms tumor

Also called Nephroblastoma Embryonal malignant neoplasm of the kidney Usually diagnosed in young children Sporadic, but in 5% to 10% of patients it may be

associated with a range of genetic syndromes or congenital anomalies.

Syndromes with Estimated Wilms’ Tumor Risk > 5%

WAGR syndrome is associated with large deletion on the WT1 chromosome located on 11p13. Denys-Drash syndrome has point mutations on WT1. Beckwith- Wiedemann syndrome is a syndrome is caused by a mutation located on 11p15, also known as the WT2 gene locus.

Presenter

Presentation Notes

Syndromes associated with WT, - WAGR (WT, Aniridia, Genitourinary anomalies, and mental Retardation) - Denys-Drash syndrome : triad of congenital nephropathy, Wilms tumor, and intersex disorders resulting from mutations in the Wilms tumor suppressor (WT1) gene. (progressive renal disease, male pseudohermaphroditism, and WT) Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are two related conditions caused by mutations of the Wilms tumor gene, WT1. Both syndromes are characterized by male pseudohermaphroditism, a progressive glomerulopathy, and the development of genitourinary tumors. DDS and FS have previously been distinguished by differences in nephropathy, with DDS patients demonstrating diffuse mesangial sclerosis (DMS) in contrast to focal and segmental glomerulosclerosis (FSGS) in FS patients. - Beckwith-Wiedemann syndrome : large tongue, an abdominal wall defect and increased growth - Isolated hemihypertrophy

Gene expression in Wilms tumor

Disruption of differentiation of the precursor cells of the kidney may result in Wilms tumor formation. Several molecules are associated with nephrogenesis and tumorigenesis. The available evidence suggests that the delicate balance in the expression pattern of these molecules during embryogenesis is the determinant of nephrogenesis and that disturbance in the expression leads to tumorigenesis. The differential expression of selected molecules is depicted beside each triangle (red: higher, green: lower). n: nuclear positivity of protein. Signaling pathway. This knowledge may lead to new perspectives in the design of more effective anticancer therapies for WT.

PRECURSOR LESIONS OF WILMS TUMOR (NEPHROGENIC RESTS)

WT is generally considered to arise from precursor lesions, which are cellular rests persisting after the embryologic development of the kidney is complete.

Renal organogenesis is usually complete by GA 36 wk. In some cases, however, part of the metanephric

mesoderm may not undergo full differentiation and maturation and may persist after birth as “nephrogenic rests”.

Presenter

Presentation Notes

Renal organogenesis is usually complete by 36 weeks of gestation by which time all the metanephric blastema has fully differentiated into renal parenchyma. In some cases, however, part of the metanephric mesoderm may not undergo full differentiation and maturation and may persist after birth as nephrogenic rests.

Diagrams depicting the various patterns of distribution of nephrogenic rests within the kidney

A, *Perilobar rest (PLNR)

B, *Intralobar rest (ILNR)

C, Panlobar rest D, Diffuse hyperplasic perilobar rest

nephrogenic rests : up to 1% of normal kidneys, but 30% to 40% of kidneys with sporadic WT, and in almost 100% of cases with bilateral WT

The risk of malignant transformation is much higher in the ILNRs as compared with the PLNRs. Perilobar rests show a strong association with synchronous bilateral WT, whereas ILNRs tend to be associated with metachronous tumors.

Presenter

Presentation Notes

The preneoplastic nature of nephrogenic rests is supported by the fact that some of the genetic abnormalities that characterize the various types of WT are also present in the nephrogenic rests. May also have an association with a variety of syndromic conditions and congenital anomalies The risk of malignant transformation is much higher in the ILNRs as compared with the PLNRs. Perilobar rests show a strong association with synchronous bilateral WT, whereas ILNRs tend to be associated with metachronous tumors.

Intralobar rests (ILNR) -mutations or deletions in WT1 (11p13) gene.

Germline abnormality of WT1 may be associated with WAGR syndrome (WT-aniridia-genital anomalies-retardation) or Denys-Drash syndrome (DDS).

Al-Hussain et al. Adv Anat Pathol 21(3),2014.

NEPHROGENIC RESTS

Clinical presentation Usually unilateral, mean age of 3.3 yrs 4 - 7% of cases - synchronous bilateral + younger age (mean age of 2.6 yrs) The most common clinical presentation - asymptomatic abdominal mass 1/3 - intermittent abdominal pain that may have been exacerbated by trauma,

can be a symptom of a rupture or intratumoral hemorrhage 1/4 - gross (macroscopic hematuria may occur when the tumor has extended

to the collecting system) or microscopic hematuria and is usually painless 1/4 - HTN Systemic symptoms may occur, especially if there is bleeding into the tumor

and associated anemia About 10% - pulmonary metastases at the time of diagnosis If spermatic veins are occluded, varicocele can occur and a thorough

examination of the abdomen is necessary. Varicocele is always an alarming symptom, but even more if it occurs on the right side [symptom of inferior vena cava (IVC) thrombosis] or occlusion of the right spermatic vein by the lower part of the tumor (right spermatic vein goes directly to IVC).

Physical examination

A firm, nontender mass in the abdomen Due to elevated renin levels, a follow-up of the blood

pressure is very important in WT patients. The most common intravascular tumor extension sites

are the renal vein, IVC, and atrium. Although the lung is the most common metastatic site,

respiratory symptoms are not common. Associated anomalies should be considered. : aniridia, hemihypertrophy, and genitourinary anomalies

Imaging study

Ultrasonography (US) is the primary diagnostic tool CT is recommended for WT along with US A plain chest X-ray is a routine procedure for the

evaluation of pulmonary metastases. A routine pulmonary CT is still controversial;

however, many physicians prefer the thoracic CT because of its high sensitivity.

Pathology

Histologically, - mixed pattern with variable proportions of 3 cellular components (classic pattern -triphasic) : stromal (fibrocytic, myxoid, skeletal muscle components) , blastemal (small blue cells), and epithelial (tubules, glomeruli) cell types WTs without anaplasia are designated as tumors of

“favorable histology.” The presence of anaplasia (5% of the WTs; characterized

as focal or diffuse), associated with lack of response to chemotherapy with an adverse outcome Anaplasia = presence of marked nuclear enlargement, pleomorphism, and hyperchromasia along with large atypical multipolar mitoses

E

2 different approaches for the management of this tumor In the COG protocol : surgical resection of WT is performed followed by histologic evaluation and accurate staging. This provides valuable information for identifying patients who require adjuvant chemotherapy. In the SIOP treatment protocol : treated with preop-chemotherapy (without a biopsy) to shrink the size of the tumor. This facilitates surgical resection and prevents tumor spillage during surgery.

MANAGEMENT OF WILMS TUMOR : THE 2 APPROACHES

Presenter

Presentation Notes

The 2 major groups that have contributed a great deal in refining approaches toward effective management of WT - the Children Oncology Group (COG) (previously National Wilms Tumor Study Group) in North America - the International Society of Pediatric Oncology (SIOP) in Europe

Wilms’ Tumor –Thai-POG

Prognosis

The long-term disease-free survival rate of patients with unilateral WT is now approaching 90% and is around 70% for those with metastatic disease.

For both synchronous and metachronous WTs, the prognosis is less favorable. Also, there is the potential for a reduced QoL due to renal insufficiency.

Risk stratification In recent COG trials for the treatment of FHWT, risk

stratification was based upon age at diagnosis, local and overall stage, tumor weight, and *LOH of 1p and 16q.

*tumor-specific LOH 1p in 11.3% and LOH 16q in 17.4% of patients with FHWT Patients with LOH 1p or 16q had a significantly increased risk of relapse (RR 1.56 and 1.49, respectively), stratified by stage. Age, local and overall tumor stage, histopathology, and

these tumor markers will be incorporated into the new prospective phase III COG trials for patients with WT, with the goal of optimizing survival while minimizing late effects through an individualized risk-based approach.

Presenter

Presentation Notes

Grundy et al. prospectively identified tumor-specific LOH 1p in 11.3% and LOH 16q in 17.4% of patients with FHWT. Patients with LOH 1p or 16q had a significantly increased risk of relapse (RR 1.56 and 1.49, respectively), stratified by stage. These findings have led to the incorporation of LOH into the risk stratification for FHWT. More recently, gain of chromosome 1q, present in nearly 30% of FHWT, has been demonstrated to predict an inferior EFS and OS across all stages.

Outcomes of COG studies

S. Irtan et al. Seminars in Pediatric Surgery 25 (2016)

Bilateral Wilms Tumours

Synchronous bilateral Wilms tumours (BWTs) 4% to 7% of cases younger age than unilateral WTs At least 10% of synchronous BWTs have unfavourable

histology, Up to 22% - associated with genitourinary

abnormalities, aniridia, WAGR (WT+ aniridia+ GU anomalies+ MR) syndrome, Denys–Drash syndrome, hemihypertrophy or one of the other overgrowth syndromes.

Chemotherapy

The current COG BWT study protocol : response-based protocol

Neoadjuvant chemotherapy : 3 drugs (VAD) given for 6 wks, with a provision for a further 6 wks if NSS (nephronsparing surgery) is not feasible. Surgery is mandated at week 12. *This protocol does not require pretreatment biopsies because bilateral tumours are very rarely clear cell sarcoma or rhabdoid tumours of the kidney.

SIOP : VA for preoperative chemotherapy for 8 weeks, adding doxorubicin after 4 weeks only if there is a poor response

Presenter

Presentation Notes

They are invariably WT, and therefore, biopsy does not change the therapy. In addition, anaplasia is difficult to diagnose, and biopsy may upstage the tumor and increase the chance of local recurrence.

Bilateral WT : ThaiPOG-WT-1304 Protocol Reference NWTS-5 Protocol

Initial treatment with VAD 6 weeks then re-evaluate

1. If complete disappearance of the tumor : Start regimen E (ThaiPOG-WT-1301)

2. If bilateral partial nephrectomy feasible : Definite surgery at wk 6 and follow flow 1

3. If bilateral partial nephrectomy NOT feasible, and

3.1. ≥ partial response* in both kidneys Continue VAD for 6 weeks then re-evaluate

3.1.1. if tumor completely disappear at week 12 : Start regimen D

3.1.2. if residual tumor presents : Definite surgery at week 12 and follow flow 1

3.2. < partial response* in either kidney : bilateral open biopsy at week 6 and follow flow 2

*Partial response: at least 64% decrease in volume (measure by multiply of the two longest diameters from imaging) compared to the measurement obtained at diagnosis.

Radiotherapy In BWT, radiotherapy use has decreased over the years : 57% of Pt. on NWTS-2 and NWTS-3 received renal or renal-bed irradiation, while 42 (21.4%) of the 196 renal units registered on the renal salvage procedure arm of NWTS-4 were treated with RT. Considered for abdominal stage III tumors or for stage II cases

of anaplasia with involved margins at tumor resection. Its use could come at the cost of reduced renal function,

particularly in young patients with the added toxicity of anthracycline chemotherapy. Other than cardiomyopathy and second malignant neoplasms, renal failure is the most common source of morbidity in BWT.

Presenter

Presentation Notes

Fortunately, it has been shown that anthracyclines can be omitted in Intermediate risk stage III cases in SIOP; however, this needs to be determined in stage V cases.

Prognosis - BWT

Major clinical challenge in BWTs -preservation of functioning renal tissue

Chemotherapy followed by nephron-sparing surgery

RT has largely been avoided because of fear of long-term radiation injury to the residual functioning renal mass.

Non-responsiveness may be due to anaplasia, and thus insensitivity to administered therapy, necrosis and rhabdomyomatous or mature stromal differentiation. While the second group of patients do not respond radiologically to therapy, they have improved outcomes when compared with those with anaplasia. It is thus crucial to establish the exact histology, and therefore, all such patients are best served by surgery.

Post-operative chemotherapy is based on the histology of the surgical specimen and the stage and is chosen according to the kidney with the highest risk. Cyclophosphamide, etoposide and carboplatin are added for unfavourable histology.

Presenter

Presentation Notes

Thus, the major clinical challenge in BWTs is the preservation of functioning renal tissue, while achieving cure with the minimum of therapy related morbidity. Although mortality is generally associated with progressive disease of anaplastic tumors, the emphasis of management has been increasingly placed on nephronsparing surgical approaches in an attempt to reduce ultimate renal insufficiency. Patient selection, appropriate pre- and post-operative chemotherapy, and skilful surgical techniques all contribute to excellent outcomes, where these are achievable.

Neuroblastoma

Neuroblastic tumors

It is contained within the neuroblastic tumors group, which includes:

Ganglioneuroma (benign) Ganglioneuroblastoma (intermediate) Neuriblastoma (aggressive)

Neural crest development and genesis of NB

Oncogenic events

Japanese Journal of Clinical Oncology, Volume 48, Issue 3, March 2018, Pages 214–241, https://doi.org/10.1093/jjco/hyx176

Both pheochromocytoma and NB share the same neurotrophin pathway. In familial pheochromocytoma, the TrkA pathway is suppressed by mutations of c-Ret, NF-1, VHL and SDH genes, while in NB, the same pathway is targeted by N-Myc to be suppressed, although there are no mutations in c-Ret, NF-1, VHL or SDH genes. KIF1Bβ, whose gene is mapped to chromosome 1p, is a common downstream target protein in both tumors.

Presenter

Presentation Notes

Figure 3. Both pheochromocytoma and NB share the same neurotrophin pathway. In familial pheochromocytoma, the TrkA pathway is suppressed by mutations of c-Ret, NF-1, VHL and SDH genes, while in NB, the same pathway is targeted by N-Myc to be suppressed, although there are no mutations in c-Ret, NF-1, VHL or SDH genes. KIF1Bβ, whose gene is mapped to chromosome 1p, is a common downstream target protein in both tumors. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

MEDICAL COMPLICATIONS ASSOCIATED WITH NEUROBLASTOMA PRESENTATION

Tumor lysis syndrome

Spinal cord compression

- 7 and 15 % of children with NB present with spinal cord involvement

- Chemotherapy and laminectomy : equivalent overall survival outcomes (Each therapeutic modality, however, carries inherent long-term and short term risks and should be determined on an individualized basis .)

- RT: generally reserved for progressive symptoms despite chemotherapy

Opsoclonus myoclonus

-usually ass. With NB of lower stage and have favorable prognosis

-often left with long-term neurologic deficits (eg, cognitive and motor delays, language deficits, and behavioral abnormalities)

-Chemotherapy, corticosteroids, and IV immune globulin may improve long-term neurologic outcome. Symptoms refractory to these treatments may respond to rituximab.

Presenter

Presentation Notes

Spinal cord compression is considered an oncologic emergency. Prompt resolution is important to limit permanent neurologic impairment. Neurologic recovery appears to be related to the severity of presenting neurologic deficits. In one study of 83 children with intraspinal neuroblastoma, 43 had neurologic symptoms at the time of diagnosis; complete neurologic function was recovered among 17 of 22 patients with mild symptoms (paresis alone), two of five patients with moderate deficits (paresis and bowel/bladder dysfunction), and 6 of 15 severely affected patients (paralysis); one patient with mild symptoms could not be assessed [91]. In a review of 99 children with spinal cord involvement, 71 had residual impairments after a median follow-up of eight years. The most common impairments in this population were motor function, scoliosis, and bladder function [93]. OMAS : For example, in the largest of these studies of outcome in children with neuroblastoma and opsoclonus-myoclonus syndrome, 20 / 29 children had persistent neurologic deficits .

Opsoclonus-myoclonus-ataxia syndrome (OMAS)

Also called “Kinsbourne syndrome” or “dancing eye syndrome,” OMAS consists of three main symptoms: Opsoclonus (conjugate,

multidirectional, chaotic eye movements), myoclonus (nonepileptic limb jerking that can also involve the head and face) and truncal ataxia, which cause gait imbalance. Sleep disturbance, cognitive dysfunction, and behavioral changes are often found.

Age of onset is typically seen before 3 years of age. OMAS is generally a paraneoplastic or parainfectious entity, but in

children, it is most commonly associated with occult neuroblastoma (NB) in about 50% of cases and between 2% and 3% of children with NB have OMAS.

Occasionally, it has been described with other entities as ovarian teratoma or hepatoblastoma.

J Pediatr Neurosci. 2016; 11(4)

Initial diagnostic evaluation

Diagnosing neuroblastoma

Plain film

CT scan (computerized tomography) or MRI scan (magnetic resonance imaging)

123I-MIBG (Meta-iodobenzylguanidine) scan

Bone marrow aspirate and biopsy

PET (positron emission tomography) scan

Like an MIBG scan, this scan detects neuroblastoma throughout the body after the injection of a small amount of radiation tagged to a sugar-like compound. This is especially useful in the 10 to 15 percent of cases where MIBG is not a useful diagnostic tool.

Urine VMA/HVA

Tissue biopsy

To confirm the diagnosis of relapsed neuroblastoma, and can be used to perform genetic testing for specific mutations that might be targets for new drugs

131 I-mIBG scan of a patient with stage 4 NB showing an adrenal primary tumor and

bone lesions in the femur and spine.

Diagnostic Criteria

Recommended Criteria at INSS Conference Established if: (1) Unequivocal pathologic diagnosis is made from tumor tissue by

light microscopy (with or without immunohistology, electron microscopy), and/or increased urine or serum catecholamines or metabolites

OR (2) Bone marrow aspirate or trephine biopsy contains unequivocal

tumor cellsa (e.g.,syncytia or immunocytologically positive clumps of cells) and increased urine or serum catecholamines or metabolites

BMA : Homer Wright pseudorosettes

Neuroblastoma

Image-Defined Risk Factors in Neuroblastic Tumors • Ipsilateral tumor extension within two body compartments : Neck-chest, chest-abdomen, abdomen-pelvis

• Neck : Tumor encasing carotid and/or vertebral artery and/or internal jugular vein

Tumor extending to base of skull

Tumor compressing the trachea

• Cervico-thoracic junction : Tumor encasing brachial plexus roots

Tumor encasing subclavian vessels and/or vertebral and/or carotid artery

Tumor compressing the trachea

• Thorax : Tumor encasing the aorta and/or major branches

Tumor compressing the trachea and/or principal bronchi

Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 - T12

• Thoraco-abdominal : Tumor encasing the aorta and/or vena cava

• Abdomen/pelvis : Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament

Tumor encasing branches of the superior mesenteric artery at the mesenteric root

Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric a.

Tumor invading one or both renal pedicles

Tumor encasing the aorta and/or vena cava - Tumor encasing the iliac vessels

Pelvic tumor crossing the sciatic notch

• Intraspinal tumor extension whatever the location provided that: More than 1/3 of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal.

• Infiltration of adjacent organs/structures - Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery

MYCN oncogene amplification - located on chromosome 2p. - -

Independent prognostic factor : in stage III EFS for patients with a single copy is curable 80%;for those with amplification MYCN – 20%

DNA ploidy: hyperploidy = good prognosis Nerve growth factor receptor: ligands for high –affinity tyrosine kinase receptors TRKA, TRKB, TRKC: -TRKA expression is associated with MYCN single copy, low stage and good prognosis -TRKA (-) + MYCN amplification= very poor survival Structural and numerical abnormalities of chromosome 1 Segmental alterations at chromosome 1p (loss of heterozygocity [LOH]), LOH at 11q, and gain at 17q -predict worse survival outcomes in patients without MYCN amplification / low-stage disease -the most reliable predictor for relapse in neuroblastoma tumors ALK (anaplastic lymphoma kinase) gene - important in both familial and sporadic neuroblastoma tumors - identified ALK mutations in >50% of familial ; 5%–15% of sporadic cases

Biologic and genetic features

Presenter

Presentation Notes

In addition to histology, the most powerful discriminating genomic and biologic factors are DNA ploidy, MYCN amplification and specific recurrent segmental chromosomal alterations. ALK is an established oncogenic driver of neuroblastoma causing uncontrolled cell proliferation and survival properties providing a specific molecular target for therapeutic intervention.


Molecular pathways of N-Myc regulation in growth of NB

N-Myc protein stability depends on the interaction partners. The receptor type-tyrosine kinase ALK activates downstream targets and eventually activates AKT. The activated AKT stabilizes N-Myc protein by inhibiting GSK-3β. N-CYM also stabilizes N-Myc by inhibiting the GSK3β-N-Myc interaction. N-Myc induces N-CYM expression. OCT4 and N-Myc form a positive feedback loop for their transcriptional expression. On the other hand, LIN28B inhibits miRNA let-7 and contributes to the stability of N-Myc protein. AURKA (Aurora-A) also stabilizes N-Myc protein to inhibit FBXW7-dependent N-Myc ubiquitination. Thus, many oncogenic proteins are involved in N-Myc stability. N-Myc -dependent tumor cells display symmetric cell division and occasionally show a cancer stem cell-like property.


MYCN is a key oncogene in NB. The cumulative survival curves of 343 Japanese patients according to the INSS are shown. Among these patients, 256 patients with NB in Stage 3, 4 s and 4 were further analyzed according the status of MYCN copy number.

Presenter

Presentation Notes

Among these patients, 256 patients with NB in Stage 3, 4 s and 4 were further analyzed according the status of MYCN copy number.

Prognostic segmental chromosomal alterations in neuroblastoma

International Neuroblastoma Risk Group : pretreatment classification

Pre-treatment risk classification modified by ThaiPOG

Protocol for very low/ low risk neuroblastoma (ThaiPOG-NB-13LR)

Protocol for standard risk neuroblastoma (ThaiPOG-NB-13SR)

Protocol for high risk neuroblastoma (ThaiPOG-NB-13HR)

PROGNOSIS

Treatment outcome — depends upon both tumor and patient characteristics, including stage, histology, MYCN amplification, DNA ploidy, age at diagnosis, extent and site of metastases.

An analysis of data on 8369 children with neuroblastoma from INRG database suggests:

-Tumor site : a primary adrenal tumor - a worse outcome, compare to thoracic primary after controlling for age, MYCN status, and stage. However, the biologic basis for this observation is not apparent, and it is not clear whether or how primary tumor site should be utilized for treatment decision-making. Tumor location is not included in conventional risk stratification schemes.


For high-risk NB, analysis of genetic background together with clinical symptoms and imaging diagnosis is very important. For HR, Induction therapy is generally performed by multi-agent chemotherapy. Following induction therapy, myeloablative chemotherapy with autologous SCT as consolidation therapy is performed. At this time, if residual tumor is found and if surgical gross total resection can be done, the tumor is removed at an appropriate time for local control. After chemotherapy, external beam radiation is performed for the purpose of preventing local recurrence as necessary. In recent years, performing immunotherapy and differentiation therapy is becoming standard therapy internationally. Also, various novel therapies have been tried on the ultra-high-risk group, which is thought to be hard to cure in existing treatments.

Therapeutic strategies for high-risk NBs

Presenter

Presentation Notes

Figure 9. Therapeutic strategies for high-risk NBs. For high-risk NB, analysis of genetic background together with clinical symptoms and imaging diagnosis is very important. If it is judged to be a high-risk NB in the INRGSS classification, induction therapy is generally performed by multi-agent chemotherapy. Following induction therapy, myeloablative chemotherapy with autologous stem cell transplantation as consolidation therapy is performed. At this time, if residual tumor is found and if surgical gross total resection can be done, the tumor is removed at an appropriate time for local control. After chemotherapy, external beam radiation is performed for the purpose of preventing local recurrence as necessary. In recent years, performing immunotherapy and differentiation therapy is becoming standard therapy internationally, but in Japan it has not yet been confirmed with regulatory approval. Also, various novel therapies have been tried on the ultra-high-risk group, which is thought to be hard to cure in existing treatments. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Novel therapies Development of new methods to treat high-risk neuroblastoma is an active area of research in pediatric oncology. In general, novel treatments are given within a clinical trial because risks of such treatment are not fully known. Examples of therapies under investigation include:

●Immunotherapies such as targeted autologous T-cells , and neuroblastoma vaccines

●Targeted therapy with drugs that act through known genetic mutations (eg, anaplastic lymphoma kinase [ALK]-inhibitor ) or induce apoptosis (eg, fenretinide )

●Modifiers of the tumor microenvironment such as antiangiogenic agents or bisphosphonates ●Iodine-131-metaiodobenzylguanidine (MIBG), which is generally used in conjunction with autologous peripheral blood stem cell rescue

Antibody therapy for cancer has potential to combine specific targeting with a range of effector mechanisms to produce potent anti-tumor responses. Antibody-based treatments are growing in success for adult cancers but have shown limited efficacy for pediatric cancers. Pediatric solid tumors have a lower mutation load that their adult counterparts and pose a unique set of challenges compared to hematological malignancies and to adult solid tumors. Whilst a number of antibodies have been subject to clinical trials in pediatric patients the response tends to be limited and there is need to identify patients most likely to benefit. The role of antibodies in combination with conventional chemotherapy and new emerging therapies is a developing field that could provide new opportunities.

Dendritic Cell-Based Cancer Immunotherapy Targeting Wilms’ Tumor 1 for Pediatric Cancer

Investigations evaluating the potential treatment of these cancers using therapeutic vaccination with an active dendritic cell (DC)-based immunotherapy are also being conducted.

Novel Therapy

Presenter

Presentation Notes

Dendritic cells and other immune cells in the cancer environment. Human leukocyte antigen (HLA) molecules harbor cancer antigen peptides, which induce DC binding with receptors on CD8+ killer and CD4+ helper T cells, leading to anticancer immune responses. In contrast, immune suppressor cells, such as regulatory T cells, tolerogenic DCs, and myeloid-derived suppressor cells, suppress autoreactive and cancer-derived mechanisms. (Original figure by Shimodaira S.) Preliminary study suggests that DC vaccination targeting WT1 administered during the course of standard cancer therapies may be both feasible for and well tolerated by patients with neuroblastoma and WT. The study findings indicate that induction of acquired immunity by targeting WT1 was detected by immune monitoring with tetramer analysis during the course of DC vaccination, confirming the positive results for this proof-of-concept investigation in pediatric patients. The results also suggest that WT1-DC vaccination may prolong the survival of pediatric patients with neoplasms. In contrast, it was not clearly determined whether there was an improvement in patient prognosis following WT1-DC vaccination because both patients died due to disease progression. Therefore, the efficacy and safety of DC vaccination should be determined by phase I/II prospective trials enrolling larger numbers of patients with pediatric neoplasms.

Thank You

Queen Sirikit National Institute of Child Health

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