Clinical immunotherapeutic approaches have taken many forms. Amongst the 
earliest were attempts to immunize the patient with disrupted tumor mixed 
with BCG as an adjuvant. These crude mixtures produced severe local 
reactions but led to detectable - albeit transient - tumor response (SJCRH 
protocol 1982). Other immunotherapy attempts have used monoclonal 
antibodies (MAbs) directed against neuroectodermal restricted antigens such 
as GD2. These MAbs are usually coupled to toxins or to radionucleotides and, 
again, tumor responses are reported. 18 " 23 Finally, efforts have been made to 
recruit T cell dependent and independent cytotoxic effector mechanisms. 
These efforts have largely focused on recombinant cytokines such as IL-2 
which stimulate the immune system, 24 or agents such as IFN-y, which may 
render the neuroblastoma cells more immunogenic to cytotoxic T cells by 
increasing their expression of Class I MHC molecules. 25 " 28 There is no doubt 
that these approaches increase cytotoxic effector function against 
neuroblastoma cell lines in vitro, although the evidence that tumor growth may 
be similarly affected in vivo is more scanty. 29 ' 37 
3.2 Improving Immune Attack 
Considered altogether, the observations above argue strongly for further 
exploration of immunomodulation as a means of neuroblastoma therapy. 
Recent animal data suggest one novel route by which this effect can be 
achieved. Transfection of tumor cell lines with cytokine genes has been shown 
to substantially increase their immunogenicity. Tumor doses normally able to 
produce progressive tumor growth instead act as a vaccine. 38 " 44 They generate 
an immune response sufficient to reject the modified cells, and the response 
generated is also sufficient to reject non-transduced tumor cells administered 
concomitantly or shortly thereafter. These effects appear to be far more potent 
than those of low-dose intralesional cytokine injection. Because the quantity 
of cytokines produced by these transduced tumor cells is so small, systemic 
levels are low. Consequently, there appear to be none of the adverse effects 
associated with the administration of high systemic doses of cytokines that are 
otherwise needed to induce anti-tumor responses. Cytokine gene transfection 
has now been shown to generate tumor immunity against several different 
transplantable animal tumor lines, including the neuroblastoma derived line 
C1300. 28,29 Moreover, the effects are obtainable with a number of different 
cytokines including IL-l-alpha, TNF, IL-2, IFN-Gamma, IL-4, and IL-7. 38 " 45 
3.3 Mechanisms By Which Immunity Is Enhanced 
The mechanisms by which this approach enhances tumor immunity are 
uncertain. Transduced cytokines may act by increasing recruitment of cytotoxic 
T cells (e.g. IL4) 44 or of CD4 positive cells (e.g. TNF and IL7), 40,45 or they 
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