Very little is known about the basis for the success or failure of adoptive-immunotherapy (AIT), but with increased insight into the anti-tumor mechanism(s) of adoptively transferred effector cells, it may be possible to improve considerably this therapeutic modality. Thus, with the objective of evaluating and improving the efficacy of IL-2-activated NK cells as effector cells in AIT of cancer, the ability of these cells to localize into tumors following adoptive transfer will be investigated, and their anti-tumor effect in vivo against established metastases will be analyzed. Based on previous work in syngeneic rodent models of lung and liver metastases, it is hypothesized that while a certain number of A- NK cells must probably localize into the malignant tissue in order to induce its regression, the number might differ depending on the location of the metastases and on their histological type. Furthermore, while localization of A-NK cells in the malignant tissues appears to be a prerequisite for therapeutic effect, it might not along guarantee therapeutic efficacy. It is predicted that the success of A-NK cells in AIT will depend on both the delivery of sufficient numbers of effector cells specifically to the malignant tissue, and the maintenance of the anti-tumor activity of the injected effector cells. To test this prediction and the associated hypotheses, the following will be examined: a) the ability of A- NK cells to localize into rodent experimental metastases in lungs, livers, peritoneal cavity, and subcutaneous tissue; b) The relationship in various organs between the density of tumor- infiltrating A-NK cells and therapeutic efficacy; c) The influence of tumor heterogeneity and vascularization on the ability of A-NK cells to localize at sites of tumors; d) The functional status of tumor-infiltrating A-NK cells and f) the possible presence of factors in the tumor milieu which might downregulate or damage the A-NK cells, and e) Strategies for counteracting the inhibitory effect of intratumoral suppressor factors, and the possibility to obtain high intratumoral concentrations of IL-2 by the use of long- lived Peg-IL-2 instead of short-lived regular IL-2. The results of there investigations should help to identify the optimal conditions for A-NK cell-based AIT of cancer and provide indications of the key parameters to consider and assess in analogous trials of clinical AIT for patients with metastatic cancer.
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