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Expert Review of Clinical Pharmacology

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Dinutuximab for the treatment of pediatricpatients with high-risk neuroblastoma

Jaume Mora

To cite this article: Jaume Mora (2016): Dinutuximab for the treatment of pediatricpatients with high-risk neuroblastoma, Expert Review of Clinical Pharmacology, DOI:10.1586/17512433.2016.1160775

To link to this article: http://dx.doi.org/10.1586/17512433.2016.1160775

Accepted author version posted online: 02Mar 2016.Published online: 21 Mar 2016.

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Dinutuximab for the treatment of pediatric patients with high-risk neuroblastomaJaume Mora

Department of Pediatric Onco-Hematology and Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu,Barcelona, Spain

ABSTRACTNeuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patientspresenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-yearsurvival rate for HR-NB remains below 40%, with the majority of patients suffering relapse fromchemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease andclinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid dis-ialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a,human-mouse chimeric ch14.18 and 3F8. Anti-GD2 MoAb induces cellular cytoxicity against NB and ismost effective when effector cells like natural killer cells, granulocytes and macrophages are amplifiedby cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18(Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMAapproved dinutuximab (UnituxinR) in 2015 for the treatment of patients with HR-NB who achieved atleast a partial response after multimodality therapy.

ARTICLE HISTORYReceived 14 December 2015Accepted 29 February 2016Published online21 March 2016

KEYWORDSNeuroblastoma; anti-GD2immunotherapy;dinutuximab; GM-CSF;Interleukin 2; chimericantibodies; orphan drugs;children’s cancer; Unituxin

Disease background

Neuroblastoma (NB) is the most common extracranial solidtumor of childhood, with 50–60% of patients presentingwith high-risk (HR) NB by means of clinical, pathological,and biological features [1]. Currently, therapy for HR-NBincludes induction treatment with chemotherapy and sur-gery, consolidation therapy with high-dose multi-agentchemotherapy rescued with autologous stem cell trans-plantation (ASCT) and radiation therapy, and maintenancetherapy to manage minimal residual disease (MRD).Intensive induction chemotherapy and aggressive surgeryhave improved remission rates in young patients [2–4];results have been modest in adolescents in whom NB isespecially chemoresistant [5,6]. Despite intensive multimo-dal therapy, long-term survival rates for HR-NB remain at30–40%. The complete eradication of NB is rarely achievedand the majority of patients with HR-NB suffer a relapsefrom chemorefractory residual tumor cells [7].

Postsurgical use of local radiotherapy helps control MRD inthe primary site [8]. Myeloablative therapy with ASCT has beenthe most common approach for eradicating MRD in distantsites [9]. A randomized CCG study yielded improved resultsusing total body irradiation (TBI) within the cytoreductive regi-men of ASCT [10]. Due to toxicity concerns, TBI is no longerused [11–14], nonetheless ASCT has become the standardapproach for MRD management in HR-NB. Extensive experi-ence, however, has shown an uncertain benefit of ASCT forrefractory NB, and recent updates of overall survival (OS) dataappear to question the effectiveness of ASCT for MRD controlin HR-NB patients [15–17].

Immunotherapy

Immunotherapy has been tested over the last 3 decades as apotential strategy against systemic MRD. Most of the clinicalexperience with immunotherapy of NB has focused on mono-clonal antibodies (MoAbs) against NB cell membrane antigensincluding cell adhesion molecules NCAM and L1-CAM, B7-H3glycoproteins targeted by the 8H9 MoAb and the glycolipidsGD2, GD3, and GM3 [18–22]. In 1985, Cheung and colleaguesdescribed for the first time four MoAbs against, at the time, anunknown glycolipid antigen on the surface of human NB cells[23]. The murine IgG3 anti-GD2 MoAb 3F8 was initially devel-oped by undergoing subsequent extensive preclinical testingeventually being the first anti-GD2 MoAb to be administeredto patients with HR-NB [24].

GD2 is a ganglioside which are acidic glycolipids found onthe outer cell membrane. They are concentrated in nervoustissues where they serve as membrane receptors for virusesand are important for cell adhesion [25,26]. GD2 is biosynthe-sized from precursor gangliosides GD3/GM3 by the β-1,4-N-acetyl-galactosaminyltransferase (GD2 synthase) [27] and isexpressed in most NB regardless of stage, and is highly abun-dant, with an estimated 5–10 million molecules/cell (Figure 1)[29]. Therapeutic responses were obtained in Phase I and IIstudies of different anti-GD2 MoAbs such as 3F8, murine IgG2MoAb 14G2a, and human-mouse chimeric MoAb ch14.18[24,30–36]. Ch14.18 was constructed by combining the vari-able regions of original murine IgG3 anti-GD2 MoAb 14.18 andthe constant regions of human IgG1 (Figure 2) [38]. In a PhaseI clinical trial reported by Yu and colleagues, 10 HR-NBpatients received a total of 19 courses of anti-GD2 MoAb

CONTACT Jaume Mora jmora@hsjdbcn.org

EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2016http://dx.doi.org/10.1586/17512433.2016.1160775

© 2016 Informa UK Limited, trading as Taylor & Francis Group

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ch14.18 at doses of 10–200 mg/m2/course. One partialresponse (PR) and four mixed responses were observed innine evaluable patients [35]. Another Phase I trial of ch14.18by Handgretinger et al. used 30–50 mg/m2/day × 5 days/course, and two complete and two PR in nine patients werereported [39].

The biological activities of the anti-GD2 MoAb ch14.18 invivo have been demonstrated by the capacity of post-infusionsera to mediate complement dependent cytotoxicity [35] andantibody-dependent cellular cytoxicity (ADCC) [40,41].Pharmacokinetic and immunological studies showed the differ-ences between the anti-GD2 MoAbs; for instance ch14.18 has alonger plasma half-life [33,42] and less immunogenicity whencompared to the murine MoAb 14G2a (Figure 2). However,toxicities of all anti-GD2 MoAbs were similar in all early studies[31,32,34,35,43]. The most common toxicities include difficult totreat pain, tachycardia, hypertension, hypotension, fever, andurticaria. Many of these toxicities are dose-dependent and are

rarely noted at low dosages [35]. The pain associated with anti-GD2 therapy is similar to other neuropathic pain syndromesand is relatively opioid-resistant. Other toxicities include hypo-natremia, hypokalemia, nausea, vomiting, diarrhea, serum sick-ness, and occasional changes in pupil reaction to light andaccommodation [42,43].

Anti-GD2 immunotherapy and cytokines

By activating ADCC to kill NB, anti-GD2 MoAbs are mostefficient when effector cell populations including natural killer(NK), granulocytes, and macrophages are amplified by cyto-kines (Figure 3). Since NK cells and granulocytes are effectorsfor ADCC, the cytokines IL-2 and GM-CSF were administered incombination with anti-GD2 MoAbs to enhance their activity.

GM-CSF has been shown both in vitro and in vivo toenhance antitumor immunity through direct activation ofmonocytes, macrophages, dendritic cells, and ADCC [57], andindirect T-cell activation via tumor necrosis factor, interferon,and IL-1 (Figure 3) [44,46–49,57,58]. GM-CSF may enhancefunctions of cells critical for immune activation against tumorcells, alone or with other cytokines or MoAbs, making it animportant agent in cancer biotherapy.

GM-CSF-dependent ADCC was studied in 34 patients with avariety of tumors post-ASCT including 3 with NB [50]. A sig-nificant increase in monocyte-mediated ADCC following GM-CSF therapy was documented. GM-CSF has the potential foramplifying anti-GD2 MoAb antitumor activity in patients via itseffects on granulocytes and tissue-based macrophages.Granulocyte production is only transiently suppressed withchemotherapy and GM-CSF increases numbers of circulatingneutrophils and eosinophils but does not affect complementlevels, and is well tolerated [45]. Granulocytes from patientsreceiving chemotherapy and from normal volunteers are effec-tive in mounting ADCC against NB cells via non-oxidativemechanisms, and GM-CSF enhances this cytotoxicity [44,46–50]. Eosinophilic infiltration of some cancers has favorableprognostic significance, and eosinophils exhibit potent antitu-mor activity in animal models. Activated monocytes-macro-phages efficiently phagocytose NB cells and exposure in vitroor in vivo to GM-CSF primes monocytes-macrophages forgreater antineoplastic cytotoxicity [44,46–49]. GM-CSFenhances the proliferation, maturation, and function of anti-gen-presenting cells. This includes antigen processing andpresentation by macrophages and dendritic cells effects thatmight promote induction, or antitumor activity, of an idiotypicnetwork [44,46–49].

Importantly, the addition of GM-CSF to anti-GD2 MoAbshas led to remarkable responses in patients with refractoryNB [57,59,60]. The analysis of 53 patients with bone marrow(BM) disease refractory to conventional treatment showed that85% achieved BM complete remission (CR) and 9/14 hadnormalization of MIBG scans after therapy with MoAb3F8 + GM-CSF [60]. Toxicities were similar to those observedwith Phase I studies of MoAb 3F8 alone. Subsequently, a PhaseII trial compared the efficacy of intravenous (iv) versus sub-cutaneous (sc) GM-CSF in combination with MoAb 3F8 inpatients with refractory NB. sc GM-CSF showed better efficacyas compared to iv administration. Retrospective review of the

Figure 1. Neuroblastoma tissue cryosection (5 µm) immunofluorescence stain-ing of the cytoplasmic membrane (in green) with anti-GD2 antibody (1:800; BD,US). Intense and universal staining of all neuroblastic cells is seen reflecting theestimated 5–10 million GD2 molecules per cell. Nuclei counterstaining per-formed with 406-diamino-2-phenylindole (DAPI), showing in blue. For protocoldetails see Acosta S. et al [28].

Figure 2. Schema depicting the composition of different monoclonal antibodies(MoAb). Murine (in red) IgG2a 14G2a is a switch (from original IgG3b) variant of themurine anti-GD2 MoAb 14.18. Chimeric Ch14.18 was constructed by combining thevariable regions of original murine (in red) IgG3b anti-GD2 MoAb 14.18 and theconstant regions of human (in blue) IgG1. The original murine IgG3 MoAb 3F8 (notshown) was recently humanized (hu3F8) based on complementarity determiningregion grafting technology (consult reference [37]) and is currently in Phase I/IIclinical trials. The human IgG molecule is shown in blue.

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experience with MoAb 3F8 plus sc GM-CSF and oral cis-reti-noic acid (CRA) showed a 5-year progression-free survival (PFS)rate of 62% and OS of 81% in patients with HR-NB treated infirst remission [60]. Nevertheless, a final proof of the contribu-tion of GM-CSF has not been tested in a randomized trial.

IL-2 (Aldesleukin) causes activation of NK cells, generationof lymphokine-activated killer cells and augments ADCC(Figure 3) [41,51–56]. An early Phase II trial with IL-2 showeda modest antitumor effect as a single agent [61]. IL-2 wasadministered to children with refractory solid tumors and noantitumor effects were observed in children with sarcomas orNB, whereas one of five children with renal cell carcinomahad CR. IL-2 was administered post-ASCT in a variety ofdiseases including NB [56,62] to eradicate the residual malig-nant cells via immune activation. At the time, the CCG-0935Phase I study of MoAb ch14.18 + GM-CSF [57] was amendedto substitute IL-2 for GM-GSF in alternate cycles [58]. Afterengraftment, patients were given ch14.18 at 40 mg/m2 withGM-CSF (Courses 1 and 3) or 20 mg/m2 with IL-2 (Course 2).However, an increase in toxicities was observed includingpain, fever, capillary leak, O2 requirement due to capillaryleak, hypotension, mild reversible increased hepatic transa-minases, and infection. Subsequently, the antibody dose waschanged to 25 mg/m2 for both the GM-CSF and IL-2 cyclesand the IL-2 dose was reduced in an attempt to decreasecapillary leak. A total of 25 patients were enrolled. The MTDof MoAb ch14.18 was determined to be 25 mg/m2/day for4 days alternated with 4.5 × 106 U/m2/day of IL-2 for 4 days.IL-2 was also administered at a dose of 3 × 106 U/m2/day for4 days starting 1 week before MoAb ch14.18. Two patientsexperienced dose-limiting toxicity due to ch14.18 and IL-2.Common toxicities included pain, fever, nausea, emesis, diar-rhea, urticaria, mild elevation of hepatic transaminases, capil-lary leak syndrome, and hypotension. These findingsindicated that MoAb ch14.18 in combination with IL-2 wastolerable in the early post-ASCT period. It is relevant to note

that overall, the reports using IL-2 for the treatment of HR-NBwere feasibility and toxicity studies in the post-ASCT settingand were not designed to answer antitumor efficacy[57,58,61–64]. The most recent data challenge the use of IL-2 on the basis of a randomized trial using long-term infusionof cho14.18 combined with or without sc IL-2 for relapsed orrefractory NB patients [65]. The addition of IL-2 increasedpain and did not enhance anti-GD2 cytotoxicity which there-fore did not support the use of IL-2 as a co-stimulatorycytokine for anti-NB purposes.

The convincing proof of anti-GD2 immunotherapy

Although MoAb 3F8 plus sc GM-CSF and oral CRA without IL-2in a series of single-arm studies showed an unprecedentedPFS and OS among patients with HR-NB [60], the definitiveproof of efficacy for anti-GD2 immunotherapy could not beascertained until a randomized control study was carried out.The Cooperative German Neuroblastoma trials NB90 and NB97with the antibody ch14.18 showed initially controversialresults. Antibody ch14.18 was applied as consolidation treat-ment in pilot patients of the NB90 and all HR patients of theNB97 trials. Early analysis did not demonstrate reduction ofthe event-free survival (EFS) [43]. A longer follow-up analysis,however, suggested a benefit of antibody ch14.18-based con-solidation therapy compared to no consolidation therapy onEFS and OS [66]. The 9-year EFS rates were 41%, 31%, and 32%for ch14.18, NB90 maintenance chemotherapy, and no conso-lidation, respectively (p = 0.098). Antibody ch14.18 treatmentas consolidation improved the long-term outcome comparedto no additional therapy (p = 0.038) [66].

In 2010, the Children’s Oncology Group (COG) reported arandomized Phase 3 study in which 226 patients with HR-NB inremission after ASCT were randomized to receive immunother-apy or CRA alone [67]. Patients on the immunotherapy arm

Figure 3. Anti-GD2 immunotherapy of neuroblastoma based on the innate immune system. In the presence of anti-GD2 MoAbs neuroblastoma cells becomesusceptible to natural killer (NK) cell mediated antibody-dependent cell mediated cytotoxicity (ADCC); granulocyte mediated ADCC; and monocyte-macrophagemediated cytotoxicity. GM-CSF enhances antitumor immunity through direct activation of (monocytes) macrophages, dendritic cells and granulocytes [44]. GM-CSFincreases the numbers of circulating neutrophils and eosinophils [45] and GM-CSF enhances the ADCC of granulocytes against neuroblastoma cells [43,45–49]. IL-2activates NK cells generating lymphokine-activated killer (LAK) cells augmenting ADCC [41,51–56].

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received MoAb ch14.18 at 25 mg/m2/day for four consecutivedays in five consecutive 4-week cycles; GM-CSF at 250 µg/m2/day for 14 days (starting 3 days before ch14.18) in cycles 1, 3,and 5; IL-2 at 3.0 × 106 IU/m2/day for 4 days in week 1 and at4.5 × 106 IU/m2/day in week 2; and CRA at 160 mg/m2/day inthe last 2 weeks of all six cycles. Patients in the standardchemotherapy group received CRA at 160 mg/m2/day in thelast 2 weeks of all six cycles. At a median follow-up of 2.1 years,MoAb ch14.18 recipients (n = 113) had significantly higher EFSrates (66 vs. 46%; p = 0.01) and OS rates (86 vs. 75%; p = 0.02)compared with standard therapy recipients (n = 113). Sincethen, a Phase 3 safety trial (NCT01041638; ANBL0931) in newlydiagnosed HR-NB patients who achieved at least PR to induc-tion therapy and received consolidation with ASCT (n = 105)was conducted with maintenance treatment for all patientswith MoAb ch14.18 (5 cycles) in combination with GM-CSF(cycles 1, 3, 5), IL-2 (cycles 2, 4), and CRA (6 cycles). Updatesfrom the original data have shown a consistent 2-year EFS andOS rates of 74% and 84%, respectively [68]. However, the 4-year(from randomization) EFS rate was not anymore significant(p = 0.1) but the 4-year OS rate still remained significantlyimproved (p = 0.02) with immunotherapy [69].

From chimeric MoAb ch14.18 to dinutuximab(unituxin®)

In July 2010, United Therapeutics Corporation (UTC) initiated aCooperative Research and Development Agreement (CRADA)with the National Cancer Institute (NCI), USA to collaborate onthe late-stage development and commercialization of MoABch14.18. As such, under the CRADA, UTC had exclusive rightsto the technical information required to manufacture compar-able MoAb ch14.18 in the murine myeloma cell line SP2/0.Since then, UTC has developed the manufacturing process toproduce MoAb ch14.18 (named dinutuximab) comparable tothat from the NCI and on a commercial scale [70]. UTC hassponsored one Phase 2 study with dinutuximab in combina-tion with GM-CSF, IL-2, and CRA for HR-NB patients, ProtocolDIV-NB-201, designed to compare the pharmacokinetic profileof ch14.18 manufactured by two independent facilities; UTCand NCI. This study also compared the safety and toxicityprofile of UTC-manufactured dinutuximab versus NCI-manu-factured ch14.18. On 10 March 2015, the US FDA and on the14 August 2015, the European Medicines Agency (EMA)-approved iv dinutuximab, in combination with GM-CSF, IL-2,and CRA for the treatment of pediatric patients with HR-NBwho achieved at least PR with prior first-line multi agent,multimodality therapy. Dinutuximab is now Unituxin®, a regis-tered trademark from UTC.

The recommended dosage of dinutuximab is 17.5 mg/m2/day administered iv over 10–20 h for four consecutive days fora maximum of 5 cycles. The infusion of dinutuximab is to beinitiated at a rate of 0.875 mg/m2/h over 30 min and the ratecan be increased gradually, as tolerated, to the maximum rateof 1.75 mg/m2/h. Unituxin® is supplied as a sterile solution insingle-dose vials containing 17.5 mg/5 mL (3.5 mg/mL) in20 mM histidine, 150 mM NaCl, 0.05% Tween 20 at pH 6.8.Dinutuximab should be diluted with 0.9% sodium chloride forinjection prior to iv infusion and the required dose withdrawn

from the vial and the exact volume for the 17.5 mg/m2/daydose injected into a 100 mL bag of 0.9% sodium chloride. Thesupplied dinutuximab does not require filtration during pre-paration nor does it need to be protected from light duringadministration. Vials should be stored in the original containertightly closed at 2–8°C. Dinutuximab is stable at room tem-perature for at least 24 h when diluted to a concentrationbetween 0.044 and 0.56 mg/mL; however, the final dosageform should be prepared immediately prior to administrationas there is a maximum infusion time of 20 h. The minimuminfusion time is 10 h. Stability data were conducted utilizing aniv bag composed of polyvinyl chloride and bis(2-ethylhexyl)phthalate (DEHP). No data are available on the stability ofdinutuximab in polypropylene syringes and polyolefin ivbags (freeflex®), within the range of 0.044–0.56 mg/mL [71].

The pharmacokinetics of ch14.18 was assessed in a Phase Itrial in 10 children with NB and 1 adult with osteosarcoma[34], and a pharmacokinetic analysis of 14 children [72] parti-cipating in the pivotal Phase 3 trial [67]. A population pharma-cokinetic analysis was based on a clinical study (NCT01592045)in 27 children with HR-NB who received 5 cycles of treatmentwith dinutuximab 17.5 mg/m2/day as an iv infusion over10–20 h for four consecutive days every 28 days in combina-tion with GM-CSF, IL-2, and CRA. In this study, the observedmaximum plasma concentration of dinutuximab was11.5 mcg/mL, mean volume of distribution at steady state5.4 L, clearance 0.21 L/day (which increased with body size)with a terminal elimination half-life 10 days [73].

Expert commentary

It has taken precisely 30 years from the discovery of anti-GD2antibodies in 1985 by Cheung and colleagues [23] to the US andEU regulatory agencies approval of dinutuximab in 2015.Although we should congratulate this extraordinary advancefor a rare, orphan disease with such poor prognosis, many issuesremain unresolved with several uncertainties for the future.

Dinutuximab has been approved in combination with GM-CSF, IL-2, and CRA in the context of post-ASCT. Recently, anupdate of the initially reported long-term OS advantage forASCT in the randomized CCG study [15] was shown to nolonger support the OS advantage for ASCT [16]. Therefore,the corrected results do not support the long-standing recom-mendation of ASCT as the systemic consolidative treatmentfor HR-NB patients. In this context, the value of immunother-apy as the sole modality for managing MRD should berevisited.

The role of each of the cytokines with which dinutuximabhas been approved remains to be clarified. IL-2 has not shownantitumor activity when used as a single agent against NB andthe significant toxicity associated to its use should promotereevaluation. No studies have been performed using dinutux-imab and GM-CSF alone; therefore, a study of sc GM-CSF alonewith dinutuximab would be of great interest. Furthermore,cytokines such as IL-15 have shown similar immune activityprofiles as of IL-2 and do not cause capillary leak syndrome[74]. Future developments should include combinations ofdinutuximab with selected new cytokines with a better toxi-city profile to enhance ADCC.

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The Phase III study showing improved 2-year EFS andreported in 2010 has been updated by the COG investigators[68,69]. The improvement in EFS appears to decline over timeand the final results on OS are still pending of longer follow-up.On the other hand, improved OS of HR-NB patients experiencingmultiple recurrences is currently possible if an active surveillanceprogram to detect earlier and smaller relapses is implemented.Therefore, long-term OS may now become a better endpoint toevaluate results for HR-NB than EFS, since the equivalencebetween relapse and lethality may no longer hold true. In thiscontext, the importance of anti-GD2 immunotherapy in improv-ing OS remains to be formally definitively proven.

Last, but not least, the market price of dinutuximab in the USAwas recently set at $150,000 per treatment (five cycles). This is, byall means an abusive cost for a drug that has been developed atthe expense of tax-payers in academic centers in the USA. Themarket price is now being negotiated in Europe, country bycountry, but it will not be cheap. The consequences of such aremultiple, including that most children worldwide will remainexcluded from access to this ‘novel’ therapy. Protecting childrenis to make sure they readily have access to the best treatmentsfor deadly diseases like HR-NB and it should be a priority ofgovernments to avoid unethical prices for orphan diseases.

Five-year view

Cancer Immunotherapy has revolutionized the adult cancerfield in recent years and was labeled the year discovery in2013. Drugs targeting specific processes of the T-cell func-tion have been developed and shown extraordinary anti-tumor effects in selected tumor types, mainly melanoma.The so-called immune checkpoint inhibitors represent thefirst in class type of drugs that can be developed to modifyT-cell response against cancer cells. It is said that immunol-ogy has come to an age where it meets oncology and all theunderstanding that has been gathered over the past30 years studying anti-GD2 immunotherapy will help indevising better and more potent agents against pediatrictumors. We have learnt that native immunotherapy is criti-cally distinct from adoptive immunotherapy and a child’simmune system relies heavily on the innate system. Theanti-GD2 MoAb experience has been the leading spear inthis field which I predict will rapidly provide more potentand less toxic agents. The recent initial description of potentbivalent GD2 and CD3-bispecific antibodies to redirect Tcells for enhanced anti-GD2 therapy is one such exam-ple [75].

Key issues

● Neuroblastoma is the most common extra cranial solidtumor of childhood, with 50–60% of patients presentingwith HR features.

● The complete eradication of NB is rarely achieved withconventional multimodality therapy and the majority ofpatients with HR-NB will relapse from chemorefractory resi-dual tumor cells.

● Anti-GD2 MoAb immunotherapy has become a clinicallyrelevant strategy against chemorefractory MRD.

● Anti-GD2 MoAb activate ADCC to kill NB response moreefficiently when effector cell populations of the innateimmune system are amplified by cytokines.

● MoAb ch14.18 (Dinutuximab) is a chimeric anti-GD2 anti-body produced in the murine myeloma cell line SP2/0.

● In the first trimester of 2015, the EMA and the FDAapproved dinutuximab, in combination with GM-CSF, IL-2,and CRA, for the treatment of pediatric patients with HR-NB.

● Unituxin® is the registered trademark from UnitedTherapeutics Company.Dinutuximab is the first and only approved drug so far for

the treatment of neuroblastoma.

Financial and competing interests disclosure

The author has no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as:• of interest•• of considerable interest

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16. Errata. J Clin Oncol. 2014;32:1862–1863.•• In a surprisingly brief format, the COG authors of the 2009

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