Syngeneic Models

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Syngeneic models of neuroblastoma, most frequently derived from the C1300 tumor, have been used to probe the role of immunotherapy. This tumor arose spontaneously in the spinal cord region of a strain-A mouse (Ishizu et al. 1994; Ziegler et al. 1997) and as a subcutaneous implant shows local invasion but rarely metastasizes. A variant of C-1300, TBJ, grows more rapidly and metastasizes extensively, and C-1300 cells inoculated into a subcutaneously translocated spleen gives rise to hepatic metastases. Against C-1300 tumors both rIFN-g and rIL-2 prolong tumor latency, and enhance tumor lysis in vitro by natural killer cells. The variant neuro-2a tumor has also been used to evaluate the role of expressing both B-7-1 costim-ulator and IFN-g. This resulted in upregulation of expression of class-1 MHC and a CD8-positive T-cell response that effectively induced tumor rejection (Katsanis et al. 1996). A variant of C-1300, NX31T28, engineered to express GD2 ganglioside has been used to evaluate biodistribution and activity of a novel fusion protein consisting of mouse chimeric anti-GD2 antibody ch14.18 fused to IL-2 (Lode et al. 1999). This fusion protein, but not the antibody alone or IL-2 plus antibody, was effective in suppressing development of bone marrow and liver disease. The same group showed that CD8+ T cells genetically engineered to produce a single chain IL-12 fusion protein significantly protect syngeneic A/J mice from disseminated neuroblastoma growth (to bone marrow and liver) (Lode et al. 1998a). Local release of cyto-kines in the tumor microenvironment is the mechanism thought to be responsible for inhibition of malignant growth and thus successful therapy. The NX31T28 model engineered to express IL-12 has also been used to induce CD8 positive-dependent protective immunity, prevented growth of wild-type cells, and eradicated established disease. The same model as been used to evaluate anti-GD2 antibody conjugat ed to the cytotoxic antibiotic calicheamycin 011 (Lode et al. 1998b). Other approaches evaluated in syngene-ic models include immunotherapy with a modified DNA vaccine where mice were immunized with a tyrosine hydroxylase-based DNA vaccine enhanced with the posttranscriptional regulatory acting RNA element derived from the woodchuck hepatitis virus in combination with an antibody-cytokine fusion protein ch14.18-IL-2. This DNA vaccine was delivered using attenuated Salmonella typhimurium and administered by oral gavage (Pertl et al. 2003). This facultative intracellular parasite that colonizes the liver has been shown to accumulate within extrahep-atic malignancies (Soto et al. 2004). Other researchers have investigated the use of IL-12 or IL-2 plus IL-18 transduced dendritic cells as vaccines for neuroblas-toma treatment (Redlinger et al. 2003a,b), the effect of cytokine expression on neuroblastoma growth (Siapati et al. 2003), and alteration in tumors recurrent after suboptimal dosing of a humanized IL-2 im-munocytokine targeted to the GD2-ganglioside. The antitumor effect of retinoic acid on the susceptibility of neuroblastoma to CTL-mediated killing has recently been reported to act through stabilization of MHC class-1 complexes, and independently of IFN-g or TNF-a (Vertuani et al. 2003).

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