innate and the adaptive systems , both capable of recognising and eliminating tumour cells . Mechanisms to remove tumour cells are primarily cellular and include CD8 + or effector T lymphocytes and natural killer ( NK ) cells . The innate immune response includes NK cells and NK-like T lymphocytes , and is responsible for the first non-specific response line , a defence system with mechanisms that operate in a matter of a few hours or days . In addition to providing direct response to tumours , these cells are important for preparing the adaptive immune response by releasing cytokines that facilitate the activation of T lymphocytes . The adaptive immune response takes several days to develop but is highly specific in its response against antigens and has long-term memory capacity . Once activated , the T lymphocytes develop a very powerful cytotoxic response . These cytotoxic T lymphocytes ( CTLs ) are capable of killing any cell expressing the antigen bound to major histocompatibility complex ( MHC ) class A molecules . These cells enable a long-range and memory anti-tumour response .
Neuroblastoma is an ideal malignancy target for immunotherapy because it derives from developing neural crest cells and thus continues to selectively express lineage-specific cell surface markers that are not widely present on mature , non-embryonic tissues . Spontaneous , innate anti-tumour immunity in neuroblastoma has been suspected because some neuroblastomas can spontaneously regress . 8 However , an active adaptive immunity against neuroblastoma has been difficult to demonstrate in HR patients . The large tumour bulk of neuroblastomas and their rapid proliferation overwhelm the immature immune system of the child . Besides , a paucity of somatic mutations makes neuroblastoma poorly immunogenic , and this tumour has developed a sophisticated immunosuppressive microenvironment to ensure that no effective T-cell immunity can develop or become functional . 9
Immunotherapy has been tested over the last three decades as a potential strategy against MRD in HR neuroblastoma . Most of the clinical experience has focused on mAbs against cell membrane antigens . In 1985 , Cheung and colleagues described for the first time four mAbs against , at the time , an unknown glycolipid antigen on the surface of human neuroblastoma cells : GD2 . 10 Most recent efforts have focused on the discovery of novel cell surface molecules that can be targeted with novel protein-based or cellular immunotherapeutic approaches . One recent example is the identification of the glypican family member 2 ( GPC2 ) as being highly and selectively expressed on most neuroblastomas . 11 GPC2 seems to be required for neuroblastoma proliferation and experiments in vitro and in vivo show that it can be targeted with a GPC2-directed antibody – drug conjugate potently cytotoxic to GPC2-expressing neuroblastoma cells . 11
Targeted immunotherapy is an important clinical advance in the treatment of high-risk neuroblastoma
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Disialoganglioside GD2 is a sialic acidcontaining glycosphingolipid expressed primarily on the cell surface membrane and plays an important role in the attachment capacity of neuroblastic cells . 12 In normal human tissues , GD2 expression is restricted to neurons , skin melanocytes and peripheral pain fibres . GD2 is biosynthesised from precursor ganglioside GD3 / GM3 by the b-1,4 N-acetylgalactosaminyltrasferase ( GD2 synthase ) and is abundantly expressed in most neuroblastomas regardless of age or stage . 13 Two intravenous ( IV ) anti-GD2 IgG antibodies have been tested extensively in the clinic : chimeric 14.18 ( ch14.18 ) and mouse 3F8 .
Phase I and II studies of murine IgG2 mAb 14G2a , murine 3F8 and human – mouse chimeric mAb ch14.18 showed clinical responses . 14 Ch14.18 was constructed by combining the variable regions of original murine IgG3 anti-GD2 mAb 14.18 and the constant regions of human IgG1 . The biological activities of the anti-GD2 mAb ch14.18 in vivo have been demonstrated by the capacity of post-infusion sera to mediate complement-dependent cytotoxicity ( CDC ) and antibody-dependent cellular cytoxicity ( ADCC ). Pharmacokinetic and immunological studies showed the differences between the anti-GD2 mAbs ; for example , ch14.18 has longer plasma half-life and less immunogenicity when compared to the murine mAb 14G2a . 14 The toxicity profile is common among all the clinically tested anti-GD2 antibodies and include difficult to treat neuropathic pain , tachycardia , hypertension , hypotension , fever and rash . Many of these toxicities are dosedependent , mainly pain , which is dependent on ADCC and CDC after binding to GD2-positive nerve fibres . The pain associated with anti-GD2 therapy is similar to other neuropathic pain syndromes and is relatively opioid-resistant . Other less common toxicities include hyponatraemia , hypokalaemia , nausea , vomiting , diarrhoea , serum sickness , and changes in pupil reaction to light and accommodation . 15 Importantly , studies of a radiolabelled form of murine anti-GD2 mAb 3F8 indicated that it does not cross the intact blood – brain barrier in mice and humans . 16 Long-term neurological impact of anti-GD2 therapy is still under assessment / investigation .
By activating ADCC to kill NB , anti-GD2 mAbs are most efficient when effector cell populations including NK , granulocytes , and macrophages , are amplified by cytokines . Because NK cells and granulocytes are effectors for ADCC , the cytokines IL-2 and GM-CSF were administered in combination with anti-GD2 mAbs to enhance their activity . GM-CSF has been shown both in vitro and in vivo to enhance anti-tumoural immunity through direct activation of monocytes , macrophages , dendritic cells , and ADCC and indirect T-cell activation via tumour necrosis factor , interferon , and IL-1 . 17 IL-2 ( aldesleukin ) causes activation of NK cells , generation of lymphokine-activated killer cells and augments