From Bench To Bedside

Previous reports on different animal models revealed that IL-2-activated NK cells are able to induce regression of established lung and liver tumors and metastases of different origin (Schwarz et al., 1989; Vujanovic et al., 1995; Whiteside et al., 1998; Yasumura et al., 1994). The control of tumors and metastases corresponded with an extended life expectancy. In contrast, the injection of IL-2 alone was significantly less efficient compared to an adoptive transfer of IL-2-activated NK cells. These data indicated that cytokine-stimulated NK cells exert beneficial effects on the control of tumors and distant metastases in immunocompetent and immunocompromised animals (Basse et al., 2001; Koda et al., 2003; Kondo et al., 2003).

As mentioned earlier, screening of primary human tumors and metastases derived there of revealed that Hsp70 is frequently expressed on the cell surface of malignant cell types. In contrast, the corresponding normal tissues were always found to be Hsp70 membrane-negative. Therefore, we hypothesized that membrane-bound Hsp70 might act as a tumor-specific recognition structure for the immune system. Since we observed that the cytolytic activity of NK cells in vitro could be further enhanced by incubation with IL-2 plus Hsp70 peptide TKD, we asked the question as to whether these NK cells might be superior in the eradication of tumors compared to NK cells that had been stimulated with IL-2 alone. In two independent xenograft tumor mouse models we studied the immunological effects of ex vivo IL-2/TKDactivated NK cells (Moser et al., 2002). A single intravenous (i.v.) injection of IL-2/TKD-activated NK cells resulted in a significant regression of colon tumors in SCID/beige mice. In the absence of TKD, these effector cells were less efficient in the suppression of the growth of Hsp70 membrane-positive tumors (Multhoff et al., 2000). We next studied the efficacy of IL-2/TKD-activated NK cells in the eradication of pancreatic tumors and metastases derived thereof (Stangl et al., 2006). Pancreatic carcinoma is the fifth leading cause of cancer related death in humans and is highly refractory to standard therapy. Phenotypic analysis revealed that Hsp70 is frequently present on the plasma membrane of pancreatic carcinomas including our model cell line Colo357. An orthotopic (o.t.) injection of Colo357 cells resulted in rapidly growing primary pancreatic tumors and in metastastic dissemination into the liver. In line with in vitro migration assays, IL-2/TKD-activated human NK cells had the capacity to infiltrate pancreatic tumors and liver metastases in tumor-bearing mice. These data are in line with data of the group of Yang who also showed the presence of cytokine-activated NK cells in lung metastases of immunocompetent mice (Yang et al., 2003).

We additionally analyzed life expectancy of tumor-bearing mice after a single i.v. injection of pre-activated effector cells. As summarized in Figure 3, immunod-eficient control mice showed first signs of tumor disease from day 18 onwards; the maximum survival time was 35 days. Adoptive transfer of pre-activated T cells only marginally improved life expectancy with all animals dying from progressive tumor disease on day 37. In contrast, a single injection of IL-2/TKD-activated NK cells significantly prolonged the survival of the mice, with more than 60% of the mice still alive on day 72. Thus, our in vivo mouse data imply that IL-2/TKDactivated NK cells might provide a novel therapeutic strategy for the treatment of therapy-refractory, Hsp70-positive pancreatic tumors.

As mentioned before, a tumor-selective cell surface localization of Hsp70, the major heat-inducible member of the Hsp70 group, could be correlated with an increased sensitivity to lysis mediated by IL-2/TKD-activated human NK cells,

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