HHE Haematology supplement 2018 - Page 9

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 lymphocytes develop a very powerful cytotoxic was constructed by combining the variable response. These cytotoxic T lymphocytes (CTLs) regions of original murine IgG3 anti-GD2 mAb are capable of killing any cell expressing the 14.18 and the constant regions of human IgG1. antigen bound to major histocompatibility The biological activities of the anti-GD2 mAb complex (MHC) class A molecules. These cells ch14.18 in vivo have been demonstrated by the enable a long-range and memory anti-tumour capacity of post-infusion sera to mediate response. complement-dependent cytotoxicity (CDC) and Neuroblastoma is an ideal malignancy target antibody-dependent cellular cytoxicity (ADCC). for immunotherapy because it derives from Pharmacokinetic and immunological studies developing neural crest cells and thus continues showed the differences between the anti-GD2 to selectively express lineage-specific cell surface mAbs; for example, ch14.18 has longer plasma markers that are not widely present on mature, half-life and less immunogenicity when compared non-embryonic tissues. Spontaneous, innate to the murine mAb 14G2a.14 The toxicity profile anti-tumour immunity in neuroblastoma has is common among all the clinically tested been suspected because some neuroblastomas anti-GD2 antibodies and include difficult to treat can spontaneously regress. 8 However, an active adaptive immunity against neuroblastoma has neuropathic pain, tachycardia, hypertension, been difficult to demonstrate in HR patients. hypotension, fever and rash. Many of these The large tumour bulk toxicities are dose- of neuroblastomas and dependent, mainly their rapid proliferation pain, which is overwhelm the dependent on ADCC immature immune and CDC after binding Targeted immunotherapy is system of the child. to GD2-p ositive nerve an important clinical advance Besides, a paucity of fibres. The pain somatic mutations associated with in the treatment of high-risk makes neuroblastoma anti-GD2 therapy neuroblastoma poorly immunogenic, is similar to other and this tumour has neuropathic pain developed a sophisticated immunosuppressive syndromes and is relatively opioid-resistant. Other microenvironment to ensure that no effective less common toxicities include hyponatraemia, T-cell immunity can develop or become hypokalaemia, nausea, vomiting, diarrhoea, functional. 9 serum sickness, and changes in pupil reaction to Immunotherapy has been tested over the last light and accommodation. 15 Importantly, studies of a radiolabelled form of murine anti-GD2 mAb three decades as a potential strategy against MRD 3F8 indicated that it does not cross the intact in HR neuroblastoma. Most of the clinical blood–brain barrier in mice and humans. 16 experience has focused on mAbs against cell Long-term neurological impact of anti-GD2 membrane antigens. In 1985, Cheung and therapy is still under assessment/investigation. colleagues described for the first time four mAbs By activating ADCC to kill NB, anti-GD2 mAbs against, at the time, an unknown glycolipid are most efficient when effector cell populations antigen on the surface of human neuroblastoma including NK, granulocytes, and macrophages, cells: GD2. 10 Most recent efforts have focused on the discovery of novel cell surface molecules that are amplified by cytokines. Because NK cells can be targeted with novel protein-based or and granulocytes are effectors for ADCC, the cellular immunotherapeutic approaches. One cytokines IL-2 and GM-CSF were administered recent example is the identification of the in combination with anti-GD2 mAbs to enhance glypican family member 2 (GPC2) as being highly their activity. GM-CSF has been shown both and selectively expressed on most in vitro and in vivo to enhance anti-tumoural neuroblastomas. 11 GPC2 seems to be required for immunity through direct activation of monocytes, neuroblastoma proliferation and experiments in macrophages, dendritic cells, and ADCC and vitro and in vivo show that it can be targeted with indirect T-cell activation via tumour necrosis a GPC2-directed antibody–drug conjugate potently factor, interferon, and IL-1. 17 IL-2 (aldesleukin) causes activation of NK cells, generation of cytotoxic to GPC2-expressing neuroblastoma lymphokine-activated killer cells and augments cells. 11 9 HHE 2018 | hospitalhealthcare.com