Abstract 2814: Therapeutic vaccination with GM-CSF gene-transduced iPS cells induces potent T cells-mediated antitumor immunity
Authors: Inoue Hiroyuki , Watanabe Ayumi , Narusawa Megumi , Sakamoto Chika , Hiramoto Takafumi , Miyamoto Shohei , Inoue Makoto , Takayama Koichi , Hasegawa Mamoru , Nakanishi Yoichi , Todo Tomoki , Tani Kenzaburo 
Published: May 2015

Development of a novel therapeutic modality targeting cancer stem cells (CSCs) holds great promise for the eventual eradication of cancer. It was demonstrated that CSCs shared antigenic similarities with embryonic stem (ES) cells and the vaccination using ES cells could generate antitumor immunity. However, the use of ES cells raises potential immunological and ethical issues. Recently, by the forced ectopic expression of defined transcription factors, autologous somatic cells were successfully reprogrammed to induced pluripotent stem (iPS) cells that closely resemble ESCs. We hypothesized that novel cell vaccines using mouse iPS cells genetically engineered to express the immunostimulatory cytokine of GM-CSF would cross-react CSC cells and induce long term antitumor immunity against poorly immunogenic syngeneic LLC mouse lung cancer cells. Our results of in vitro assays demonstrated that non-transmissible recombinant Sendai virus-mediated mouse GM-CSF gene transfer to iPSCs (iPS/GM-CSF) was effective to produce abundant GM-CSF in vitro and iPS/GM-CSF cells maintained their stemness in terms of morphology and antigenicity as evidenced by the expression of SSEA-1,Oct3/4 and alkaline phosphatase compared with unmodified iPS cells. Prophylactic iPSCs vaccine studies revealed that wild-type female mice subcutaneously vaccinated with irradiated iPS (ir.iPS) cells on weeks 1, 2, and 3 before the tumor challenge with LLC cells significantly suppressed the LLC tumor growth compared with untreated mice (p&lt;0.05). Importantly, mice carrying pre-established LLC tumor treated with ir.iPS/GM-CSF cells showed significantly suppressed tumor growth compared with mice treated with ir.iPS/GFP cells (p&lt;0.05). No serious adverse events were observed without any organ damages of liver and kidney. Furthermore, the antitumor effects observed in mice treated with ir.iPS/ GM- CSF cells were significantly abrogated when CD4+ T or CD8+ T cells were depleted, showing their capacity to incite T cells-mediated antitumor immunity. Lastly, we performed a cDNA microarray analysis to identify commonly upregulated genes of the putative CSCs-associated antigens as a target of iPS cells-based vaccines among LLC cells, iPS vaccine cells. Several sperm- or cell surface- specific antigens were predominantly expressed and shared between the 2 distinctive cell fractions.

Taken together, our results demonstrated that iPS cells-based vaccine could induce both prophylactic and therapeutic antitumor immunity in syngeneic mouse models, and suggested that this novel vaccine strategy may be a promising modality for cancer immunotherapy.

Citation Format: Hiroyuki Inoue, Ayumi Watanabe, Megumi Narusawa, Chika Sakamoto, Takafumi Hiramoto, Shohei Miyamoto, Makoto Inoue, Koichi Takayama, Mamoru Hasegawa, Yoichi Nakanishi, Tomoki Todo, Kenzaburo Tani. Therapeutic vaccination with GM-CSF gene-transduced iPS cells induces potent T cells-mediated antitumor immunity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2014-2814