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REVIEW ARTICLE
GD2-targeted immunotherapy and potential value of circulating microRNAs in
neuroblastoma†
Sharareh Gholamin1,2,*, Hamed Miezaei3,*, Seyed-Mostafa Razavi4,*, Seyed Mahdi
Hassanian5,6,*,Leila Saadatpour7, Aria Masoudifar11, Soodabeh ShahidSales8,# Amir Avan9,10,#
(1) Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, United
States
(2)Department of Bioengineering at California Institute of Technology, Pasadena, CA, United states.
(3) Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran
(4) Department of Neurosurgery, Stanford University, Stanford, CA, United States.
(5) Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran.
(6) Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
(7) Department of Neurology, University of Florida College of Medicine, Gainesville, FL, United States.
(8) Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
(9) Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran.
(10) Molecular Medicine group, Department of Modern Sciences and Technologies, Mashhad University of
Medical Sciences, Mashhad, Iran.
(11) Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for
Biotechnology, ACECR, Isfahan, Iran
#Corresponding Authors:
Amir Avan, PhD; Metabolic Syndrome Research Center, School of Medicine, Mashhad University
of Medical Sciences, Mashhad, Iran., Tel:+9851138002298, Fax: +985118002298; Email:
avana@mums.ac.ir & amir_avan@yahoo.com
Soudabeh ShahidSales MD; Cancer Research Center, School of Medicine, Mashhad University of
Medical Sciences, Mashhad, Iran. Tel:+9851138002298, Fax: +985118002298; Email:
ShahidSaless@mums.ac.ir
* equally contributed as first author to this study.
Running title: anti-GD2 therapy in Neuroblastoma
Grant: This study was supported by grant awarded (Amir Avan) by the Mashhad University of
Medical Sciences.
Conflict of interest: The authors have no conflict of interest to disclose
†This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
[10.1002/jcp.25793]
Received 9 January 2017; Accepted 10 January 2017 Journal of Cellular Physiology
This article is protected by copyright. All rights reserved DOI 10.1002/jcp.25793
This article is protected by copyright. All rights reserved 2
Abstract
Neuroblastoma (NB) with various clinical presentation is a known childhood malignancy. Despite
significant progress in treatment of NB afflicted patients, high risk disease is usually associated
with poor outcome, resulting in long-term survival of less that 50%. Known as a disease most
commonly originated form the nerve roots, the variants involved in NB imitation and progression
remain to be elucidated. The outcome of low to intermediate risk disease is favorable whereas the
high risk NB disease with dismal prognosis, positing the necessity of novel approaches for early
detection and prognostication of advanced disease. Tailored immunotherapy approaches have
shown significant improvement in high-risk NB patients. It has found a link between Gangliosides
and progression of NB. The vast majority of neuroblastoma tumors express elevated levels of GD2,
opening new insight into using anti-GD2 drugs as potential treatments for NBs. Implication of anti-
GD2 monoclonal antibodies for treatment of high risk NBs triggers further investigation to unearth
novel biomarkers as prognostic and response biomarker to guide additional multimodal tailored
treatment approaches. A growing body of evidence supports the usefulness of miRNAs to evaluate
high risk NBs response to anti-GD2 drugs and further prevent drug-related toxicities in refractory or
recurrent NBs. miRNAs and circulating proteins in body fluids (plasma, and serum) present as
potential biomarkers in early detection of NBs. Here, we summarize various biomarkers involved
in diagnosis, prognosis and response to treatment in patients with NB. We further attempted to
overview prognostic biomarkers in response to treatment with anti-GD2 drugs. This article is
protected by copyright. All rights reserved
Key words: Neuroblastoma, miRNAs, anti-GD2 drugs
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Introduction
Neuroblastoma (NB) is usually derived from neoplastic neuroblasts of the sympathoadrenal lineage
of the neural crest. The tumor has the propensity to arise from sympathetic ganglia and the adrenal
medulla. NB is a most common solid tumor in children. The current treatment approaches
compromise surgical resection, radiotherapy and immunotherapy (9). With grim outcome in nearly
12% of children younger than 15 years of age, high-risk NB remains as a significant disease burden
in pediatric neuro-oncology. Several studies showed that NB is a heterogeneous and complex
disease and a lot of factors such as stage of disease, age and genetic alterations involved in
progression of this malignancy (1-7). Beside genetic heterogeneity and aberrant epigenetic
regulation, abnormal expression of small non-coding RNAs (miRNAs) has revealed indispensable
role in NB establishment and resistance to current standard treatments (8-10). Different expression
of miRNAs between MYC amplified and non-amplified human neuroblastoma tumors corroborated
the role of miRNAs in neurblastoma pathogenesis (10-13). Identification of such factors opens new
insight into their implication as biomarkers in diagnosis, prognosis and therapy in NB (3).
In recent years, immunotherapy has emerged as a promising approach in treatment of multiple
cancers. Recent effective implication of monoclonal antibodies for specific targeted antigens on
cancer cells in human trials provided the grounds to further investigate the therapeutic outcome by
optimizing treatment strategies. Several reports support the ubiquitous expression of gangliosides
such as disialoganglioside GD2 on NB tumor cells, conferring its important role in tumor growth
through different mechanisms, usually executing the function as a receptor for different molecules
such as viruses, toxins, hormones and growth factors(14, 15). Monoclonal antibodies against
disialoganglioside GD2 (anti-GD2 mAbs) have shown therapeutic effects on patients with NB,
usually preventing further relapse in afflicted patients (14). To extend the therapeutic effect and
improve additional therapeutic strategies of anti-GD2 mAbs with on-time administration of the drug
and monitoring on disease progression, identification of highly sensitive diagnostic and predictive
biomarkers are of paramount importance .
This article is protected by copyright. All rights reserved 4
Together, defining novel screening paradigms for early detection of clinical disease or to enhance
the therapeutic outcomes would benefit neuroblastoma patients, particularly patients with advanced-
stage disease.
Neuroblastoma and anti-GD2 drugs
Neuroblastoma cells express high level of gangliosides on their surface(15) . Apart from high
expression of gangliosides on tumor cells surface, gangliosides are also found in microenvirment of
tumors. A number of studies has also demonstrated that gangliosides circulate in the blood stream
of patients (14-16). Several biological effects are, at least in part, linked to the presence of
gangliosides on NB cells such as: modulating cell signaling, acting as receptors, participating in
intercellular communication, tumor cell surface markers, cell cycling, and cell motility (14, 15).
Additionally, these molecules are also involved in various biological pathways that are implicated
in pathogenesis and progression of tumors (15). GD2 has a high expression on the surface of tumor
cells originating from neuroectoderm, such as NB and melanoma, while has limited expression on
normal tissues, principally in the cerebellum and peripheral nerves (14-17). Several reports
revealed that GD2 contribute to the attachment of NB cells to the extracellular matrix (15, 18, 19).
Figure 1 illustrates the structure of GD2 ganglioside. Chemically, GD2 ganglioside is: GalNAcβ1
→ 4 (Neu5Acα2 → 8) (Neu5Acα2 → 3) Galβ1 → 4Glcβ1 → 1’-ceramide. Expression of GD2 in
NB cells is more than benign tumors such as ganglioneuroblastoma and ganglioneuroma. Hence,
GD2 is known as sensitive diagnostic biomarker that contributes to distinguish NB from other
tumors (20-22). Czaplicki et al, presented GD2 as a biomarker in progression of NB where high
plasma levels of GD2 correlated with a more rapid disease progression among afflicted patients.
Besides, their results revealed that the level of GD2 ganglioside in the plasma of NB patients
declined substantially in the course of treatment (23). Because of an evident expression of GD2 on
NB cells surface and role in NB pathogenesis and progression, it potentially serves as a target in NB
therapy (16, 24). GD2 has been utilized as a target in monoclonal antibody therapy and has been the
primary target of antibody recognition in NB (20, 21, 25). Various researches demonstrated that
This article is protected by copyright. All rights reserved 5
normal tissue in brain only expression GD2 where is inaccessible to circulating antibodies. Hence,
peripheral nerves and melanocytes can be suitable target for systemic tumor immunotherapy (24,
26). Various anti-GD2 antibodies with proven safety and efficacy have been assessed in clinical
trials for NB for several years (15, 27). The application of anti-GD2 antibodies is associated with
some limitations such as inability of antibodies to treat bulky tumor and acute pain toxicity related
to GD2 expression on peripheral nerve fibers (1, 27). Researchers have tried to overcome to these
limitations through implementing several strategies such as using blocking antibodies, bypassing
complement activation, targeting of O-acetyl-GD2 derivative that is not expressed on peripheral
nerves surface in order to reduce pain toxicity (28). on the other hand, to improve and enhance anti-
tumor efficacy, the studies have designed new anti-GD2 monoclonal antibodies and fragments
associated with immunotoxins, bispecific T-cell engaging antibodies, radiolabeled antibodies,
immunocytokines, antibody drug conjugates, targeted nanoparticles and chimeric antigen receptors
(15, 29). Table 1 illustrates various anti-GD2 antibodies that are used in clinical for NB treatment.
Several reports indicated that the application of monoclonal antibodies specific to GD2 such as
chimeric 14.18 and 3F8 induce anti-tumor response via monocyte-macrophage mediated
cytotoxicity (phagocytosis), granulocyte-mediated ADCC (granulocyte-ADCC); complement-
mediated cytotoxicity (CMC) by binding to C1q; NK cell-mediated antibody-dependent cell-
mediated cytotoxicity (NK-ADCC).
Associated biomarkers which are modulated in response to the treatment
Of the reported biomarkers modulated by anti-GD2 antibodies, miRNAs have the the potential to
assist prognosis, diagnosis and therapy effect prediction in NB (36-39). Table 3 shows biomarkers
that can regulate some pathways in NB and can serve as novel biomarkers in treatment and response
to therapy in NB. As described by Tivnan et. al, nanoparticles encapsulating miR-34a and
conjugated to a GD2 antibody facilitated tumor-specific delivery following systemic administration
into tumor bearing mice. Their results demonstrated that a significantly increased apoptosis,
decreased tumor growth and a reduction in vascularisation. They demonstrated that miR-34a with
This article is protected by copyright. All rights reserved 6
multi-targets as a novel therapy led to increased levels of the tissue inhibitor metallopeptidase 2
precursor (TIMP2) proteins, accounted for the highly decreased vascularization noted in miR-34a-
treated tumors (40). Another study by Tarek et al showed that there are different response between
NB patients who lack one or more HLA ligands compared with patients who possess all HLA KIR
ligands when treated with anti-GD2 mAbs . NB patients without one or more HLA ligands had
respons better to treatment with lower rates of relapse [Reference]. Their results revealed that the
unlicensed NK cells expresses KIRs for non–self-HLA ligands in these patients can be more
effective in tumor elimination than the licensed NK cells expresses KIRs for self HLA (41). Hence,
KIR-HLA immunogenetics may be acceptable biomarkers in response to treatment and therefore
survival in patients with NB.
One of other biomarkers is minimal residual disease (MDR) that may be the utilized to response to
drugs in NB patient. Several studies demonstrated that to provide more sensitive detection of MRD
and overcome tumor heterogeneity several sets of real-time RT-PCR markers have been assessed
for MDR monitoring in NB patients. Cheung et al, revealed that bone marrow (BM) MRD may be
an early-response biomarker and a consistent independent predictor of survival after anti-GD2
therapy. In this study, BM MRD was mastered before 3F8 treatment and after cycle 2 with utilizing
assessment of four-marker panel (B4GALNT1, PHOX2B, CCND1, and ISL1) by quantitative
reverse transcription polymerase chain reaction ( qRT-PCR) (42). In other study, Hartomo et al
reported a panel including 14 genes for detecting MDR in NB patients. They validated the ability
of 14 commonly used biomarkers to detect MRD based on their expression in NB . They revealed
that the samples as MRD-positive when the expression of one of the 11 biomarkers (CHRNA3,
CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) exceeded the
normal range (43). Their result clearly manifested that the MRD detection protocol based on the
expression of a set of 11 real-time RT-PCR biomarkers in NB provide sensitive MRD monitoring
in NB patients. Further studies revealed epigenetic, molecular and genetic factors involved in NB
This article is protected by copyright. All rights reserved 7
pathogenesis and progression, presenting them as strong candidates to predict treatment response to
anti-GD2 drugs (22, 44, 45)
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Circulating biomarkers
The majority of NB patients have been diagnosed in advanced stages of this disease. Fast and easy
detection in NB patients can contribute to diagnosis and monitoring of therapeutic response in these
patients, further on paving the road to early detection of the disease (1). Moreoever, improved
detection methods and identification of powerful biomarkers can increase survival and response to
different drugs. Circulating biomarkers present in body fluids such as serum, plasma and urine are
known as powerful tools in diagnosis, prognosis and therapy in several solid tumors such as NB
(105-107). These biomarkers have a lot of advantages such as non-invasive, easy and fast detection.
Some studies revealed that there are several circulating biomarkers in NB (108, 109). Circulating
miRNA is one of them. miRNAs have significant biology roles in signaling pathways and may
induce or inhibit progression of various cancers such as NB (7, 109-115). Ramraj et al, assessed
miRNAs present in serum that involve in aggressive NB in mouse models of non-metastatic. In this
study, they examined circulating miRNAs signatures and alteration of profile them in mice bearing
favorable or high-risk disease utilizing whole genome human miRNA profiling approach. Their
result revealed that 33 miRNAs of 42 miRNAs showed a significant up regulation (>2 fold) in
animals with high-risk NB. Preferential exclusion of mouse miRNA with sequence homology blast
indicated 11 (off 33 up-regulation) unique human miRNA. Consistently, homology blasting
identified 13 (off 42 down-regulation) miRNAs (116). Proteomics is other fields that contribute to
identifying new biomarkers and help to their clinical application. The utility of proteomics-based
methodologies is such that it offers the potential of identifying signature patterns of multiple
proteins specific to a particular cancer (117, 118). Using of these techniques, previous works
showed mass spectrometry-based protein profiles/pattern differences between serum samples
among children with NB and non-cancer patients (119). In one study, identification of plasma
Complement C3 as a potential biomarker for NB using a quantitative proteomic approach. They
have demonstrated the suitability of the TH-MYCN+/+mouse model of NB for identification of novel
disease biomarkers in humans, and have identified Complement C3 as a candidate plasma
This article is protected by copyright. All rights reserved 9
biomarker for measuring disease state in NB patients (9). In other study, Sandoval et al, the
utilizing of proteomics approaches for investigating other proteins profiles as new candidate serum
biomarkers in an established animal model of advance stage human NB. Their investigations
indicated that some serum proteins differentially expressed in NB model than normal groups.
Hence, these serum proteins may be used as new biomarkers in NB patients. They showed that
investigation serum proteins profile by proteomics approaches can be utilized for monitoring in
early high-risk NB. Their results indicated that up-regulation of five mouse serum proteins (α1-
antitrypsin, α2-macroglobulin, serum amyloid A, α1-acid glycoprotein and serum amyloid P-
component) were identified in animal model of NB. Down-regulation of immunoglobulin kappa
chain constant region (Ig κ-C) was found in the serum of animal model of NB as compared to
controls (2.5-fold, p≤ 0.05). In NB patients, apolipoprotein A-IV, α1-acid glycoprotein, serum
amyloid A and haptoglobin were observed to be overexpressed (120). In all studies have not been
used anti-GD2 drugs until obtaining these biomarkers as predictive biomarkers to response to these
drugs. Hence, we suggest that these biomarkers can be used as novel biomarkers after treatment
with anti-GD2 drugs.
Drug-resistant mechanisms
Several studies revealed that treatment failure in patients with poor prognosis lead to resistance to a
diverse range of functionally and structurally unrelated cytotoxic drugs. Amplification of the N-
myc oncogene is one of main powerful biomarkers of poor outcome in NB patients (125). Various
studies approved that appearance multiple drug resistance in patients associated with amplification
of the N- myc oncogene (125-127). Mechanisms involve in amplification that effect on the
phenotype of NB are unclear. Several laboratories have investigated multidrug resistance (MDR)
properties in various malignancies (128, 129). Some reports indicated that MDR1 gene is one of
genes involve in MDR . This gene encodes P-glycoprotein(130). These studies suggested that
MDR1 have main key roles in MDR in various cancers such as NB (130, 131). MRP is another
gene involve in MDR in NB patients. This gene locates on chromosome 16p13.1 and encodes a
This article is protected by copyright. All rights reserved 10
glycoprotein . MRP functions is like P-glycoprotein and observed that this protein show multiple
drug resistance properties in several malignancies (132, 133). Some researches approved that
change expression this gene, led to observed multiple drug resistance properties in NB cells in vitro
(125, 126, 134, 135). In other study, Norris et al, revealed that there is relation between MRP
expression with poor outcome and MRP expression outcome in patients with NB (134). In another
research, Lu et al, was examined effect of the expression of p-glycoprotein (P-gp), multidrug
resistance-associated protein (MRP), and lung resistance protein (LRP) in NB patients. Their results
revealed that multidrug resistance of NB involves the combined effects of MRP, P-gp and LRP.
MRP expression may be a main factor determining prognosis in NB patients (136). In other hands,
there are not any reports that indicate pathways and genes involve in resistance of anti-GD2 drugs
in NB. Hence, these genes and new genes may be used as new options for obtaining anti-GD2 drugs
resistance markers in NB.
Exosome and NB
Exsosomes are known as one of main players in cell-to-cell communications. A number of cells
including tumor cells, stem cells, and some normal cells could release exosomes (137-139). These
nano-carriers are capable to carry a variety of molecules such as proteins, mRNAs, and miRNAs. It
has been shown that these cargos could affect on a sequence of targets in recipient cells which could
lead to change behavior cells (137-139). A large number evidences indicating exosomes released
from tumor cells could contribute to progression of tumor in various stages. These vehicles and
their cargos could have critical roles in main processes including apoptosis, angiogenesis, tumor
growth and resistance to chemotherapy present in beginning and progression of tumors (137, 138).
Various studies showed that these nanoparticles and their cargos affect on progression of NB (140).
In a study by Challagundla and et al, assessed role of exosomes containing miRNAs in resistance to
chemotherapy for NB cells (140). Their results indicated that some exosomal miRNAs such as miR-
21 and miR-155 had main roles in chemotherapy resistance by targeting TLR8-NF-кB and TERF1
This article is protected by copyright. All rights reserved 11
signaling pathways. They showed that up regulation of miR-155 associated with low levels of
TERF1 proteins. These data suggested that exosomes containing various miRNAs could be used as
diagnostic and therapeutic biomarkers in NB patients (140).
Another study, Haug and colleagues assessed potential oncogenic roles of exosomes release from
NB cells in progression of NB (141). They showed that MYCN-amplified NB cell lines released a
variety of exosome-like vesicular particles containing miRNAs . These exosomes carried various
cargos such as proteins ( e.g. CD9, CD63, and TSG101) and miRNAs ( e.g. miR-16, miR-125b,
miR-21, miR-23a, miR-24,miR-25, miR-27b, miR-218, miR-320a, miR-320b and miR-92a). These
exosomal miRNAs act oncomiRs, which could affect on a sequence of targets (e.g. TLR8, NF-kB,
STAT3 and p53) present in NB pathogenesis. These results suggested that exososomal miRNAs might
play a critical roles in progression of NB by targeting a variety of cellular and molecular targets
present in NB pathogenesis (141).
Proteins are other important cargos, which could carry with exosomes. In a study by Marimpietri et
al., indicated that exosomes released from NB cells could carry a number of proteins including
etraspanins, fibronectin, heat shock proteins, MVB proteins, cytoskeleton-related proteins,
prominin-1, basigin and B7-H3, CD9 and CD63 (142). They showed that these proteins could
anticipate in various processes such as defense response, cell differentiation, and cell proliferation.
Therefore, exosomal proteins are other options, which may be used as diagnostic and therapeutic
biomarkers in NB patients (142).
Conclusion
NB is known as a heterogenetic disease in children. In spite of obtaining many achievements in the
finding and understanding of molecular pathways and biological heterogeneity of this disease, NB
has remained a growing malignancy in children. GD2 ganglioside is known as an agent involved in
carcinogenesis and has important biology roles in NB development. Various drugs can block this
agent such as anti-GD2 drugs. The recognition of new biomarkers that associated with prognosis,
This article is protected by copyright. All rights reserved 12
diagnosis, therapy, survival, response to treatment and relapse after treatment with anti-GD2 drugs
treatment may contribute to improve and monitor of disease progression in NB afflicated patients.
This article is protected by copyright. All rights reserved 13
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progression. PLoS One. 2013;8(9).
This article is protected by copyright. All rights reserved 21
Fig 1. Schematic chemical structure of GD2 ganglioside.
Fig 2. Schematic diagram of various miRNAs network in NB tumorigenesis and metastasis
This article is protected by copyright. All rights reserved 22
Table 1. Current clinical trials testing various GD2 antibodies for treatment of NB
Antibody
Kind of
Antibody
Comments
Clinical Status
Ref
hu14.18 based
hu14.18
Humanized
Naked antibody
Phase I (NCT00743496)
(15)
hu14.18 +IL-2 + GM-CSF + NK Cells
Humanized
Naked antibody
Phase I (NCT01576692)
(15)
hu14.18+IL-2 + G-CSF + GM-CSF
Humanized
Naked antibody
Phase II (NCT01857934)
(15)
hu3F8 based
hu3F8
Humanized
Naked antibody
Phase I (NCT01419834)
(30)
hu3F8 + GM-CSF
Humanized
Naked antibody
Phase I (NCT01418495)
(15)
hu3F8 + IL-2
Humanized
Naked antibody
Phase I (NCT01662804)
(15)
3F8 based
3F8 + allogenic NK cells
Murine
Naked antibody
Phase I (NCT00877110)
(15)
3F8 + heat modified 3F8 + GM-CSF
Murine
Naked antibody
Phase I (NCT00450307)
(31)
3F8 + beta-glucan
Murine
Naked antibody
Phase I (NCT00492167)
(32)
3F8 + GM-CSF
Murine
Naked antibody
Phase II (NCT00072358)
(20)
3F8
Murine
Naked antibody
Phase II (NCT00002458)
(16)
3F8 + GM-CSF + isotretinoin
Murine
Naked antibody
Phase II (NCT01183897)
(33)
3F8 + GM-CSF + beta-glucan +
isotretinoin
Murine
Naked antibody
Phase II (NCT00089258)
(15)
ch14.18 based
ch14.18 + GM-CSF
Chimeric
Naked antibody
Phase I (NCT01418495)
(34)
ch14.18/CHO + isotretinoin + IL-2
Chimeric
Naked antibody
Phase I/II
(NCT01701479)
(15)
ch14.18 + lenalidomide + isotretinoin
Chimeric
Naked antibody
Phase I (NCT01711554)
(15)
ch14.18 + GM-CSF + IL-2
Chimeric
Naked antibody
Phase III
(NCT00026312)
(15)
ch14.18/CHO + isotretinoin + IL-2 +
G-CSF
Chimeric
Naked antibody
Phase III
(NCT01704716)
(26)
Others
8B6
Chimeric
Naked antibody, anti-O-
acetyl-GD2
Pre-clinical
(35)
MORAb028
Human
Naked antibody, human IgM
Phase I (NCT01123304)
(15)
131I-3F8 + GM-CSF + bevacizumab
Murine
Radiolabeled antibody
Phase I (NCT00450827)
(15)
131I-3F8 and 124 I-3F8
Murine
Radiolabeled antibody
Phase II (NCT00445965)
(15)
hu3F8 multistep targeting
Murine
Radiolabeled antibody
Pre-clinical
(15)
hu3F8 multistep targeting
Murine
Radiolabeled antibody
Pre-clinical
(15)
hu3F8xhuOKT3 BsAb
Murine
Antibody for pre-targeting
Pre-clinical
(15)
iC9-GD2 CAR transduced T cells
Murine
Chimeric antigen receptor
Phase I (NCT01822652)
(15)
14G2a-CAR in EBV-CTL
Murine
Chimeric antigen receptor
Phase I (NCT00085930)
(15)
hu3F8-CAR
Humanized
Chimeric antigen receptor
Pre-clinical
(15)
iC9-GD2 CAR transduced VZV
specific T cell + VZV vaccine
Murine
Chimeric antigen receptor
Phase I (NCT01953900)
(15)
This article is protected by copyright. All rights reserved 23
Table 2. Predictive biomarkers in NB
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This article is protected by copyright. All rights reserved 25
This article is protected by copyright. All rights reserved 26
Table 3. Circulating biomarkers in NB
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1 erugiF
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2 erugiF
