Successful anti-tumor responses are now thought to depend on a 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-2/pulse IL-12 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. Recent studies implicate Fas-mediated apoptotic effects in the early anti-vascular or antitumor effects. The evaluation of preclinical therapies that depend on generation of adaptive immune responses is often complicated by limitations of existing preclinical models where tumors grow relatively rapidly. We have now used the nitrosamine compound, streptozotocin to induce new low passage renal cell carcinomas(RCC)in BALB/c mice, and have characterized these tumors for etiology, morphological and functional heterogeneity, and angiogenic phenotype. These streptozotocin-induced RCC(SIRCC) tumors exhibit some morphological characteristics of human RCC, grow relatively slowly after orthotopic transplant and express a pro-angiogenic phenotype. Cloned sublines derived from these tumors exhibit considerable heterogeneity in their in vivo growth rate and metastatic progression. These models are now being used to study the mechanisms engaged by IL12/pulse IL2 and and IL18/IL2 therapies. 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 provided the rationale for a now completed non-human primate toxicology study of the IL-12/IL-2 combination, and a Phase I clinical trial of this cytokine combination recently opened by the Division of Clinical Sciences, NCI.
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