Abstract 4764: Vaccination of tumor-bearing mice with irradiated tumor cells and depot-formulated IL-2, IL-12, IL-4, GM-CSF and IFN-a eradicates the tumor cells and induces lasting immunity to the tumor

Abstract

In order to overcome the complex tumor-host interactions equally complex biological countermeasures have to be taken. By applying several cytokines in the vaccine the cytokine network is activated more efficiently then by using a single cytokine. To render the approach mote feasible, the cytokines were applied in depot Form. This allows formulation following pharmaceutical rules, and, at the same time, leads to steady release and keeps the inflammatory process active over a long period of time. Applying this concept, vaccines were designed that contained, besides irradiated tumor cells, a bouquet of cytokines in depot formulation. Due to their different biological activities IL-2, IL-4, IL-12, GM-CSF and IFNα were chosen. The sequential steps of vaccine action: The release of a multiplicity of cytokines accelerates the influx of inflammatory cells of the innate immune system. Under the influence of IL-4. GM-CSF and IL-12 released from the depot, Dendritic cells are recruited, maturated and activated under physiological conditions in situ, at the inoculation site, circumventing tedious ex vivo procedures. Tumor cell fragments generated by cells of the innate immune system are taken up by the locally generated CD86+ mature Dendritic Cells and transported to the lymph nodes where they are presented to T cells. In addition, cytokine-loaded depot particles are carried to the lymph nodes where they become involved in activation processes that are not understood yet. Due to its angiogenic activity, depot-released GM-CSF induces the sprouting of capillaries into the inoculum, thus opening the way for recirculation of activated CD4+ and CD8+ T cells into the inoculum. Depot-released IL-2 and IFNα further activate cells of the NK/NK-T cell lineage. Applying Multi-Cytokine-Depot Tumor Vaccines, we have been able to cure mice from tumors induced by injection of a lethal dose of vital tumor cells. Although the set-up of the vaccine is complex, its preparation is easy and relies on formulation following pharmaceutical principles rather than on trial and error. For each cytokine as well as for the tumor cells a specific Dose-Response-relations has been determined. We are currently preparing for the application of this concept in clinical trials. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4764.