Purpose To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-α 2a in metastatic renal cell carcinoma patients. Experimental Design Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 × 107 cells/1 mL Lactated Ringer’s solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-α 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti–renal cell carcinoma antibody and cytokine levels. Results All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4+ T regulatory cells had a strong association with outcome. Pre–IP-10 serum levels approached significance for predicting outcome. Conclusions The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.

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IntroductionA genetic alteration frequently observed in cancer tissue is the increased expression of cyclin E (1). For example, the majority of liver cancers express this protein at levels higher than in the surrounding normal tissue (2). Intriguingly, cyclin E is also able to induce DNA double-strand breaks, which may lead to genetic instability and aneuploid cells (3). Consistent with the importance of cyclin E in regulating cell proliferation and genetic stability, its expression levels are tightly controlled. In addition to transcriptional mechanisms, cyclin E levels are also regulated by posttranslational modifications that trigger the proteolytic degradation of cyclin E by cullin 1-or cullin 3-dependent (Cul1-or Cul3-dependent) ubiquitin ligases. Degradation of cyclin E by the Cul1-dependent ubiquitin ligase requires its interaction with the F-box protein Fbw7, which upon phosphorylation of cyclin E at T380 by GSK3 and T384 by cdk2 tightly binds to the protein and mediates its polyubiquitination and subsequent proteasomal turnover (4, 5). Mutations in Fbw7 have been shown to induce genetic instability, and certain types of human cancers such as T cell leukemias and cholangiocellular carcinomas frequently show alterations in this gene (6).Loss of Fbw7 also affects stem cell proliferation by depleting hematopoietic stem cells due to active cell cycling and an increase in the rate of apoptotic cell death (7-9). Conversely, expression of a stabilized version of cyclin E that can no longer be degraded by the Fbw7-dependent E3 ubiquitin ligase results in an expansion of the