Abstract 4389: Impact of regulatory T cell depletion on dendritic cell-tumor fusion vaccine immunotherapy

Abstract

Abstract A promising branch of research in cancer immunotherapy is the development of vaccines comprised of dendritic cells hybridized to tumor cells by electrofusion. Studies in numerous murine models have shown the efficacy of treatment with a dendritic cell-tumor fusion vaccine; however, this is critically dependent on systemic administration of 3rd signals such as IL-12 (Interleukin-12). Translation of these findings into the clinic will be difficult due to toxicity, morbidity, and mortality associated with IL-12 administration. Thus, alternative strategies to enhance the efficacy of fusion vaccines are needed. Regulatory T cells (Tregs) are known to suppress anti-tumor immunity. Treg depletion has been demonstrated to improve tumor immunotherapy in murine tumor models as well as some phase I clinical studies. We therefore investigated whether Treg depletion with the anti-CD25 monoclonal antibody PC61 would significantly improve dendritic cell - tumor fusion immunotherapy in a murine melanoma model. Experiments were conducted using six groups of animals: no treatment (negative control), isotypic monoclonal antibody alone (Y13), Treg depletion alone (PC61), fusion vaccine with Y13 (Fusion + Y13), fusion vaccine with PC61 (Fusion + PC61), and fusion vaccine with IL-12 (Fusion + IL12; positive control). Pulmonary metastases were established through intravenous tail vein injection of 0.25x106 tumor cells (Day 0). Three days later, an injection of 0.6x106 fusion hybrids was delivered intranodally. 250 µg of Y13 or PC61 monoclonal antibodies were delivered one day prior to vaccine delivery. Starting on the day of vaccination in the IL-12 group, 0.2 µg of IL-12 was given daily for 4 days. Three weeks after tumor inoculation, mice were euthanized and the pulmonary metastases were enumerated. The median number of metastases and standard deviation [SD] per group were the following: no treatment= 204 [50]; Y13= 220 [59]; PC61= 211 [49]; fusion+Y13= 126 [67]; fusion + PC61= 72 [74]; fusion + IL12= 1 [11]. Using the Mann-Whitney U test, there was a statistically significant reduction in the number of tumor metastases between both the fusion vaccine + Y13 group and the fusion + PC61 group (P=.0397) as well as PC61 alone group and fusion + PC61 group (P=.002). This suggests that Treg depletion can significantly augment dendritic cell-tumor cell fusion melanoma immunotherapy. Our results support the development of novel therapeutic modalities that include Treg depletion, or modulation, to enhance the efficacy of dendritic cell - tumor fusion cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4389. doi:1538-7445.AM2012-4389