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
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