262. Delivery of CCL21 to Metastatic Disease Improves the Efficacy of Adoptive T Cell Therapy

Adoptive T cell transfer has achieved a significant measure of clinical success, notably in the setting of advanced melanoma. However, therapeutic efficacy is limited by factors such as poor T cell survival post-adoptive transfer, and inefficient trafficking to tumor sites. Here we report that the chemokine CCL21 can enhance the efficacy of adoptive T cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro, and down-regulated the expression of the lymph-node homing molecule CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might be useful in recruiting, and retaining, adoptively transferred T cells to the sites of tumor growth. Mice bearing multiple metatstatic tumors stably transduced to express CCL21 survived significantly longer following adoptive T cell transfer than mice bearing non CCL-21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors per se, tumor- expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells both in vitro and in vivo, and led to the priming of anti tumor immunity following T cell transfer. To translate these observations into a protocol of real clinical utility, we demonstrated that adsorption of a retrovirus encoding CCL21 to OT-1 T cells prior to adoptive transfer, increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in a cure of metastatic disease and the generation of immunological memory in the majority of treated mice.In summary, we have shown that it is possible to deliver CCL-21 in a truly systemic manner, in a fully immuno-competent host, using adoptively transferred, antigen specific T cells, without the need to access any tumor sites for direct delivery of the CCL-21 gene. In this way, CCL-21 can significantly enhance the therapeutic efficacy of subsequently administered doses of T cells. Therefore, in addition to other manipulations, such as the use of T cell supportive cytokines, additional vaccinations and lymphodepletion, CCL-21 is a promising and novel reagent for use in enhancing the efficacy of adoptive T cell transfer protocols.