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
93 HHE 2018 | hospitalhealthcare . com
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
Disialoganglioside GD2 is a sialic acid-
innate and the adaptive systems, both capable
containing glycosphingolipid expressed
of recognising and eliminating tumour cells.
Mechanisms to remove tumour cells are primarily primarily on the cell surface membrane and
plays an important role in the attachment
cellular and include CD8+ or effector T
capacity of neuroblastic cells. 12 In normal
lymphocytes and natural killer (NK) cells. The
human tissues, GD2 expression is restricted to
innate immune response includes NK cells and
neurons, skin melanocytes and peripheral pain
NK-like T lymphocytes, and is responsible for the
fibres. GD2 is biosynthesised from precursor
first non-specific response line, a defence system
ganglioside GD3/GM3 by the b-1,4 N-acetyl-
with mechanisms that operate in a matter of a
galactosaminyltrasferase (GD2 synthase) and is
few hours or days. In addition to providing direct
abundantly expressed in most neuroblastomas
response to tumours, these cells are important
regardless of age or stage. 13 Two intravenous (IV)
for preparing the adaptive immune response by
anti-GD2 IgG antibodies have been tested
releasing cytokines that facilitate the activation
extensively in the clinic: chimeric 14.18 (ch14.18)
of T lymphocytes. The adaptive immune response
takes several days to develop but is highly specific and mouse 3F8.
Phase I and II studies of murine IgG2 mAb
in its response against antigens and has long-term
14G2a, murine 3F8 and human–mouse chimeric
memory capacity. Once activated, the T
mAb ch14.18 showed clinical responses. 14 Ch14.18
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