Earlier attempts to engage the immune system with oregovomab in ovarian cancer patients was successful in generating B-cell and specific T-cell responses in combination settings but insufficient specific immune response was produced in the mono-immunotherapy clinical trials conducted in the maintenance period following front line chemotherapy. Clinical trials looking at the time to relapse (progression free interval) failed to demonstrate a treatment effect for this application, although long term survival outcomes were not obtained. In contrast, two clinical trials conducted in the front line and recurrent settings in which tumor antigen was at higher levels and cytotoxic compounds were also administered demonstrated stronger cellular and humoral immune responses. Furthermore evidence regarding dose schedule and choice of cytotoxic agent has been generated, and preclinical combination chemo-enhanced immunotherapy studies confirmed the human findings in transgenic murine and human in vitro model systems. These studies have demonstrated that generation of a tumor-antigen specific CD8 IFN-gamma T-cell response (as performed in the laboratory of Whiteside/Butterfield, University of Pittsburgh) is associated with significantly improved clinical outcomes in terms of progression free and overall survival. Two reports have been published by OncoQuest investigators detailing these findings in the front line (Braly et al., J Immunother 2009) and also in second-line recurrent disease settings (Gordon et al., Gyn Oncol 2004). Preclinical studies done in a MUC1 transfectoma mouse model indicate a combination of anti-MUC1 antibody, AR20.5, in combination with gemcitabine can indeed enhance immune response and survival (Hollingsworth, personal communication). Thus in both MUC1 and CA125 associated malignancy, the OncoQuest antibody technology when used in combinatorial settings and with available tumor antigen has the capacity to significantly enhance specific tumor immunity. Furthermore, recent insights into the use of additional non-specific immune modulatory approaches (such as TLR agonists) may further enhance this biological effect (Nicodemus et al., Am J Obstet Gynecol 2010). This biological outcome has been correlated with clinical benefit in recently approved immunotherapy products.