A secondary analysis using a Cox multivariable regression analysis of overall survival, which adjusted for prognostic factors known to influence survival, met the criteria for statistical significance. The HR observed in this Cox multivariable regression analysis was similar to that seen using the same analysis in D9901. The overall AE profile observed in Phase 3 studies (D9901 and D9902A) was similar to that observed in the Phase 2 studies, although infusion-related fevers and rigors appeared to be more common. The following infusion-related AEs occurred more frequently ( P ≤ 0.05) in subjects treated with sipuleucel-T than those treated with placebo: chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. However, these events generally resolved within 1 to 2 days. Sipuleucel-T was subsequently evaluated in a randomized placebo-controlled Phase III trial in patients with asymptomatic and minimally symptomatic CRPC (IMPACT Trial) and demonstrated statistically significant survival advantage of 4.1 months. Main eligibility criteria included the presence of metastatic CRPC, lack of visceral metastases, and lack of significant pain defined by the use of narcotic analgesics. The compound was well-tolerated with brief febrile infusion reactions constituting the main side effect. Sipuleucel-T did not induce significant PSA or objective responses but there was evidence of immune activation targeting prostate antigens. Specifically titers against PA2024 that exceeded 400 at any time after baseline were observed in 66.2 % of patients in the Sipuleucel-T and 2.9% in the placebo group. Patients with positive antibody titer against PA2024 had improved survival as compared to patients who did not generate such response. Antibodies against PAP were observed in 28.5% of patients treated with Sipuleucel-T and 1.4 % in patients in a placebo group. At week 6, T-cell proliferation responses (stimulation index>5) to PA2024 were seen in 73% of patients in the Sipuleucel-T group and 12.1% in the placebo arm. Responses to PAP were observed in 27.3 % in the Sipuleucel-T group and 8.0% in the placebo group. Based on the results of this trial Sipuleucel-T was approved by Food and Drug Administration for the treatment of patients with metastatic CRPC. 2.5 STAT3-Activity STAT3 activity in tumor-associate myeloid cells is known to orchestrate tumor angiogenesis (Kujawski JCI 2008). Our recent studies assessed whether STAT3 activity in the tumor microenvironment can limit the antitumor effect of the local tumor irradiation. We observed that tumor irradiation can enhance, rather than interrupt, STAT3-mediated crosstalk between cancer and myeloid immune cells. The radiation- induced cell death led to release of endogenous TLR agonists for TLR9, including mitochondrial DNA (mtDNA), which in turn sustain high STAT3 activity in myeloid cells. We demonstrated that STAT3 activation post-irradiation is mostly TLR9-mediated and depends on rapid expression of cytokines inducing Jak/STAT3 signaling, such as IL-6. Cancer cell repopulation was significantly delayed in TLR9- deficient mice compared to wild-type animals, which correlated with reduced STAT3 activation in tumor- infiltrating myeloid cells and impaired reconstitution of tumor blood vessels. In addition, lack of TLR9 Page 14 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 expr ession correlated also with decreased numbers of lung metastases suggesting the role of TLR9 signaling in tumor dissemination. We further verified the negative role of STAT3 for the efficacy of radiation therapy using conditional STAT3 gene deletion in myeloid cells as well as STAT3 silencing using CpG-STAT3siRNA. Both approaches confirmed that elimination of tumorigenic TLR9/STAT3 signaling axis in tumor-associated myeloid cells prevents cancer recurrence following the local tumor irradiation. Targeting STAT3 using immune cell-specific CpG-siRNA strategy is likely to provide a future therapeutic approach to support cancer radiotherapy. In this study we will perform the exploratory analysis of the effect of radiation therapy on the levels of pSTAT3 in Peripheral Blood Mononuclear Cells (PBMCs) and serum levels of proinflammatory cytokines and TLR9 ligands. 3.0 Patient Eligibility Prior to the initiation of screening procedures, the purpose and procedures of the study will be explained to each subject, and each subject will then sign an Institutional Review Board (IRB) approved consent form.