Abstract 751: Vaccination with MUC1-pulsed dendritic cells prolongs survival in triple transgenic mice with orthotopic ovarian tumors
Authors: Budiu Raluca A. , Elishaev Esther , Brozick Joan , Chu Tianjiao , Predoiu Silviu , Edwards Robert P. , Vlad Anda M. 
Published: June 2012

Background: Despite improvements in surgical techniques and chemotherapy approaches, ovarian cancer continues to be associated with a low 5 year survival. Sustained improvement in the development of new therapeutic approaches depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. MUC1 oncoprotein is a tumor -associated antigen expressed by all epithelial ovarian tumors and a valuable target for immunotherapy.

Objective: To test the therapeutic efficacy of a MUC1-based vaccine using dendritic cells matured in type 1 polarizing conditions (DC1). This vaccine was administered to novel triple transgenic conditional tumor-bearing mice, which we recently generated and characterized.

Methods: Our new triple transgenic mice (MUC1+/−LSLKrasG12D/+PtenloxP/loxP) co-express a Kras oncogenic mutation and a Pten deficiency (previously described) and carry the MUC1 transgene encoding for the human MUC1 tumor-associated antigen, driven by the endogenous Muc1 promoter. We induced tumors in n=21 double and n=18 triple transgenic (Tg) mice by AdCre injection under the ovarian bursa, during survival surgery. Five of the 18 mice were vaccinated with 3x 103 DC1, grown in GM-CSF, matured with IL-4, IFNγ, LPS and Poly I:C (DC1 cocktail) and pulsed with 10ug/ml 100mer MUC1 peptides (DC1-MUC1). The vaccine was administered s.c 3 times, 2 weeks apart starting at week 5 after AdCre injection. We measured natural and vaccine- induced immune responses via ELISA, multicolor flow cytometry, and real-time PCR arrays.

Results: Intrabursal administration of AdCre in the double (KrasPten) and triple (MUC1KrasPten) Tg mice leads to de novo ovarian epithelial tumors. The tumors occur in the injected ovary only, spread throughout the abdominal cavity and on the diaphragm and may be accompanied by hemorrhagic ascites. Characterization of the tumor environment revealed increase PGE2 accumulation in ascites and overexpression of COX2 at the tumor site and throughout the injected side of the female genital tract. Despite the histomorphologic similarities of MUC1KrasPten and KrasPten mice neoplasms, only the triple Tg tumors express MUC1, mimicking even closer the human disease. The overall survival was shorter in triple Tg compared to double Tg mice (average of 65 and 82 days, respectively, p = 0.105) pointing out to important MUC1 roles in ovarian tumor biology. DC1-TnMUC1 vaccine significantly increases overall survival (p = 0.003) and decreases CD4+FOXP3+ Treg cells in spleen, compared with non-vaccinated tumor-bearing mice (p &lt; 0.001).

Conclusions: MUC1KrasPten mice represent the first preclinical model for orthotopic ovarian carcinogenesis expressing the human MUC1 antigen. This preclinical data provides a platform for using MUC 1 vaccine as a form of immunotherapy in ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 751. doi:10.1158/1538-7445.AM2011-751