Successful anti-tumor responses most likely depend on critical interplay between adaptive T cell-mediated and innate non-T cell-mediated immune mechanisms. Transplantable mouse renal and autochthonous mammary carcinoma models have been used to demonstrate that the systemic administration of the combination of IL-12/pulse IL-2 yields enhanced antitumor effects against even well-established metastatic cancers. The antitumor effects of IL-12/pulse IL-2 are rapidly initiated by a mechanism that includes the upregulation of antiangiogenic and apoptosis-associated genes in the tumor site and the destruction of tumor vasculature-associated endothelial cells. Thus, an early anti-neovascular response may be a critical initial component in the process of tumor rejection. Both the early antiangiogenic responses as well as the ultimate regression of these tumors depend on the presence of a functional IFN-gamma gene and a functional Fas/FasL pathway. In addition, recent results have demonstrated that potent adaptive responses can be induced by the use of IL-2 in combination with anti-CD40. These effects are dependent on IFN-gamma and at least partially IL-12. We have used streptozotocin, an antibiotic and diabetogenic nitrosamine compound derived from Streptomyces achromogenes to induce new transplantable kidney tumors in BALB/c mice. Single or multiple doses of streptozotocin induced kidney tumors in up to 25% of mice by 50 to 90 weeks of age, with up to 18% histologically characterized as renal cell carcinomas. Several transplantable lines were obtained from the renal carcinomas, and one of these lines was subsequently cloned. The initial tumor isolates and sublines were histologically re-confirmed to be renal carcinomas, and all grew progressively, but slowly (mean survival times 57 to >100 days), in vivo after intrarenal implant. None of the primary isolates or sublines revealed mutations in either the VHL or Ras genes, although karyotype analysis and chromosome painting revealed the consistent presence of a submetacentric chromosome resulting from the fusion of chromosomes 16 and 19. Biological characterization of these tumors revealed several features analogous to the growth of human kidney cancers, including a propensity for the formation of lung metastases and high vascularity. This hypervascularity is evident by both gross and microscopic analysis and correlates with the expression of several pro-angiogenic genes. Overall, the features of orthotopic transplantability, slower in vivo growth (relative to the rapid growth rates of other transplantable mouse kidney tumors), propensity for lung metastases and hypervascularity may make these tumors valuable models for the study of new therapeutic strategies based on anti-neovascular agents and antitumor cytokines. Overall, our results to date suggest that successful biological therapy of cancer may depend on a complex combination of immune-mediated and immune-dependent (i.e. antiangiogenic) events. These preclinical results have been translated into an ongoing clinical trials of IL-12/pulse IL-2 in the Center for Cancer Research, NCI.
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