Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

16.6
Neuroblastoma
16.6.1
Treatment with ch14.18±IL-2 Immunocytokine
The rationale for constructing an IL-2 immunocytokine with a human/mouse chimeric
antiganglioside GD2 antibody (ch14.18±IL-2) was based on encouraging data
obtained in clinical trials of passive immunotherapy of neuroblastoma patients with
human/mouse chimeric antibody ch14.18 and with murine antiganglioside GD2
antibody 14G2a plus rhIL-2. Specifically, passive immunotherapy in adjuvant settings
with ch14.18 antibody resulted in a response rate of over 50 % in phase I and
phase I/II clinical trials, including several long-term and complete remissions of
stage four patients [81]. Data from a phase I/Ib clinical trial using a combination
therapy with murine anti-GD2 mAb 14.G2a and rhIL-2 also showed antitumor activity
[82]. Thus, preclinical experiments with a recombinant ch14.18±IL-2 immunocytokine
in a syngeneic immunocompetent mouse model were a logical sequel, which
was established by using GD 2-positive NXS2 murine neuroblastoma cells in syngeneic
A/J mice [83]. Importantly, following s.c. and i.v. injections, NXS2 cells metastasized
both spontaneously and experimentally to sites typical for human neuroblastoma,
including bone marrow, liver, lymph nodes and adrenal glands. The characterization
of this model was further extended by two findings. First, MYCN, a very important
oncogene for neuroblastoma used as a most predictive prognostic marker
[84±86]Ëwith a proven involvement in neuroblastoma pathogenesis [87], was found in
NXS2 cells. Second, the expression of the noradrenaline transporter was established
in NXS2 cells which was previously characterized as the intracellular uptake system
for meta-iodobenzylguanidine ([ 131 I]mIBG) [49], an experimental radionuclide currently
under clinical evaluation for the adjuvant treatment of neuroblastoma [88±91].
The positive signal for this transporter in NXS2 cells suggested that this model
might be a useful tool for the evaluation of this type of radiotherapy as a single modality
or in combination with other adjuvant therapies including immunotherapy or
anti-angiogenesis.
16.6.2
Immunocytokine Treatment of Bone Marrow and Liver Metastases
16.6 Neuroblastoma
The therapeutic effect of the ch14.18±IL-2 immunocytokine observed in both, spontaneous
and experimental bone marrow and liver metastasis models was achieved
only in A/J mice that received this immunocytokine [83]. Significantly, these animals
had no macroscopic liver disease and revealed a lack of detectable metastasis to the
bone marrow, determined by tyrosine hydroxylase RT-PCR detecting one tumor cell
in 100 000 naive bone marrow cells. A Kaplan±Meier analysis of mice following induction
of spontaneous bone marrow and liver metastases indicated a tripling in lifespan
in 50% of the animals only when treated with the immunocytokine. This was
in contrast to the lack of increased survival in control groups, which received an
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