We now have ten separate members of the extended IL-1 family [IL-1Fx] identified including IL-18 as the most distantly related member. The biologic role of many of these cytokines is unclear but IL-1alpha/IL-1F1, IL-1beta/IL-1F2, IL-18/IL-1F4, and IL-1H4/IL-1F7 promote antitumor responses when used as genetic constructs. We have previously shown in vitro that the antitumor effects of rIL-18 delivered in murine tumor models can be mimicked with coculture of murine DCs, NK cells, tumor, T-cells and IL-18, leading to the generation of tumor specific T-cells. IL-18 gene therapy is dependent on DC and NK cells, Fas signaling but not on NKT cells nor IFNgamma nor IL-12. A novel IL-1 homologue, IL-1H4/IL-1F7 also mediates antitumor effects, which are IL-12-dependent and Fas dependent, demonstrating a mixture of biologic effects attributable to IL-12 and IL-18. We will now explore these cytokines in human in vitro studies with DC and NK cells interacting to promote a T-cell response to human melanoma. We will thus explore whether the other IL-1 homologues including IL-1alpha, IL-1beta, IL1RA, IL-1F5/IL-1F9 and IL-1H4 [IL-1F7] mediate similar or dissimilar effects in in vitro culture. We will evaluate the critical components of the coculture system in human in vitro cultures with human melanoma. We will also evaluate whether IL-12 production is enhanced in an IFNgamma dependent manner in such cultures generating successful development of specific T-cells in NK and DC cultured with tumor. We will contrast the role of the IL-1 family members in cooperation with Project I to assess similar readouts in murine melanoma and the relative contributory roles of the TNF family members and the extended IL-12 family members with Project II. An important question will be to test these premises in vivo in patients with melanoma and we will assess this in innovative clinical protocols assessing local tumor response in patients with multiple cutaneous melanoma metastases and contrast with ex vivo strategies in patients with melanoma in Project II. We will test these notions in the following Specific Aims:
Aim 1. Evaluate IL-1 homologues and their ability to promote NK and DC activation, polarization;
Aim 2. Develop specific T-cell reactivity to autologous and MHC matched melanoma in vitro with IL-1 homologues;
Aim 3. Integrate NK and DC biomarkers with IL-1 homologues and proteomic assays in treated melanoma patients and Aim 4. Administer ANK/DC to melanoma patients in sequential clinical trials.

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National Cancer Institute (NCI)
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University of Pittsburgh
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