2003; Gadducci, Cosio et al. 2005). Phase III studies of both main tenance and consolid ation therapeutic interventions have not had an impact on overall survival (Mei, Chen et al. ; Foster, Brown et al. 2009; McGuire 2009; Pe corelli, Favalli et al. 2009). It is therefore pertinent that expression of all three immunosuppressive TGF  isoforms is increased in ovarian tumor as compared with normal ovarian tissue (Henriksen, Gobl et al. 1995; Bristow, Baldwin et al. 1999) with significant increases in TGF 1 in both primary (2.9 fold; p ≤ 0.002) and recurrent (4.4 fold; p ≤ 0.002) ovarian cancer (Bristow, Baldwin et al. 1999). Secreted TGF β from ovarian cancer cells generate immunosuppr essive Treg cells (CD4+CD25+) from peripheral CD4+CD25- cells (L i, Ye et al. 2007). Both Treg tumor infiltration as Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 14 well as the granzyme B+/FOX3p+ ratio are associated with outcome in those patients treated with neoadjuvant chemotherapy (Polcher, Braun et al.). The contribution of optimal surgical cytoreductive surgery to prognosis may be due, in part, to the associated reduction in circul ating Tregs (Napoletan o, Bellati et al. 2009). In a recently described transgenic LSL-K-ras G12D/+p53loxP/loxP murine model of induced metastatic ovarian canc er in the setting of a mature immune system (Scarlett, Rutkowski et al.), a shift in dendritic cell phenotype from immunostimulatory to immunosuppressive was shown to be due to tumor-cell derived TGFβ 1 and PGE2 both of which were f ound to be secreted at high levels in advanced tumors (Scarlett, Ru tkowski et al.). Further, TGF  has been linked to the emergence of cisplatin resistance (Li, Balch et al. 2009). Furin, an upstream regulator of TGF β activity, is a member of the subtilisin-like proprotein convertase family. Proteolytic cleavage by furin is required for TGF β convertase activation (i.e. pro-TGF β TGFβ). All three of the TGF β isoforms contain the RXXR motif at their cleavage site albeit with different amino acid sequences (Kusakabe, Cheong et al. 2008). High levels of furin mRNA and furin are widely expressed in human tumors and, specifically, in ovarian tumors (Page, Klein-Szanto et al. 2007). The presence of furin in tumor cells likely contributes significantly to the maint enance of tumor directed, TGF β-1 peripheral immune tolerance (Pesu, Watford et al. 2008). According to the serial immune function analyses by Coleman (Coleman, Clayton et al. 2005), five of nine patients with Stages III-IV ovarian adenocarcinoma who achieved post-chemotherapy remission retained the capacity of CD8 + T-cell responses to a panel of 11 viral peptides restricted by at least six common HLA class I alleles, whereas four patients wi th disease progression displayed low or reduced responses at different stages of treatment. Chemotherapy produced no apparent effect on naïve (CD45RA+CCR7+), central memory (CD45RA-CCR7+), or effector memory (CD45-CCR7-) T-cells. Background on Transforming Growth Factors beta (TGF β) 1.4 Transforming growth factors beta (TGF β) are a family of multi-functional proteins that regulate the growth and function of many normal and neoplastic cell types (Sporn, Roberts et al. 1986; Massague 1987; Border and Ruoslahti 1992; Jachimczak, Bogdahn et al. 1993). TGF β is synthesized as a prepro-TGF β precursor, processed in the Golgi apparat us with removal of the propeptide and secreted as either the small latent complex (SLC) or with latent TGF β-binding protein (LTBP) as the large latent comp lex (LLC) (Li, Wan et al. 2006). Following dissociation from the matrix associat ed latent complexes, the dimeric TGFβ activates a tetrameric TGF β receptor complex comprised of TGFβ RII and TGFβRI (ALK5) resulting in the phos phorylation of Smad2 and Smad 3 which translocates to the nucleus comple xed with Smad4 where a number of Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 15 transcription factors are engaged. TGF β2 signal transduction has been found to affect the expression of more than 20 different genes (Baker and Harland 1997; Heldin, Miyazono et al. 1997; Stiles, Ostr ow et al. 1997; Yingling, Datto et al. 1997). TGF β exerts a wide range of effects on a variety of cell types and has been shown to stimulate or inhibit ce ll growth, induce apoptosis and increase angiogenesis (Jennings, Kaariainen et al . 1994; Merzak, McCrea et al.