Analysis of sequence homology with other known proteins reveals a low risk of cross-reactivity of immune responses. GM-CSF is a multilineage factor that may also activate mature granulocytes and macrophages, and may activate quiescent APCs. Sipuleucel-T is an autologous cell product consisting of APCs loaded with prostate antigen PA2024. Preparation of sipuleucel-T entails isolating quiescent APCs from a subject’s peripheral blood leukapheresis product by buoyant density techniques and then culturing them for approximately 2 days in the presence of PA2024. The culture medium does not contain serum or exogenous cytokines. During the culture process, APCs specifically and selectively pick up antigen (PA2024) and differentiate into antigen loaded APCs capable of presenting antigen to T cells. These APCs thus represent the cells responsible for the biological activity of sipuleucel-T. Other cell populations in sipuleucel-T co-purify with APCs during buoyant density centrifugation, but do not incorporate or present antigen, and are therefore referred to as “non-APCs.” After the culture period, the cells are washed and suspended in Lactated Ringer’s Injection, USP. The final preparation of PA2024-loaded APCs is designated sipuleucel-T. Sipuleucel-T is placed in a refrigerated package and transported to the clinical site for infusion. 8.1.2 Leukapheresis and Collection of Quiescent APCs Leukapheresis and collection of blood cells to generate sipuleucel-T is performed at the facility contracted by the manufacturer Dendreon and is analogous to that for autologous blood transfusions. Briefly, subjects undergo a standard 1.5 to 2.0 blood volume leukapheresis to harvest peripheral blood mononuclear cells (PBMCs; primarily lymphocytes and monocytes). Prior mobilization with a colony- stimulating factor is not performed. Immediately after collection, the leukapheresis product is transported to a regional manufacturing facility 8.1.3 Quality Testing Quality control (QC) testing is performed at several time points during the manufacturing process and on samples of the final product. If the final product passes all required release tests, an approval to infuse the product (Cell Product Disposition Form) is faxed to the infusion center. If a cell product does not meet Dendreon quality specifications, Dendreon will contact the infusion center by telephone and by fax. Page 27 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 D endreon will provide instructions for product return or destruction of cell products that are not approved or not infused. 8.1.4 Storage and Time Limitations The infusion of Sipuleucel-T must begin prior to the expiration time indicated on the product label. Expir ed cell products must not be infused. 8.1.5 Administration The administration of Sipuleucel-T is performed in the City of Hope infusion clinic. Subjects are premedicated with acetaminophen and an antihistamine such as diphenhydramine prior to the infusion. After the site receives the Cell Product Disposition Form indicating the cell product is approved, the infusion is administered over approximately 60 minutes through an intravenous (IV) line suitable for blood transfusion (without a cell filter). Subjects are observed for at least 30 minutes following the infusion. 8.1.6 Toxicity The safety evaluation of Sipuleucel-T is based on 601 prostate cancer patients in the Sipuleucel-T group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. Almost all (98.3%) patients in the Sipuleucel-T group and 96.0% in the control group reported an adverse event. The most common adverse events, reported in patients in the Sipuleucel-T group at a rate ≥ 15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. In 67.4% of patients in the Sipuleucel-T group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life- t hreatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the Sipuleucel-T group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the Sipuleucel-T group compared with 3.6% of patients in the control g roup. The most common (≥ 2%) Grade 3-5 adverse events reported in the Sipuleucel-T group were back pain and chills. Serious adverse events were reported in 24.0% of patients in the Sipuleucel-T group and 25.1% of patients in the control group. Serious adverse events in the Sipuleucel-T group included acute infusion reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. Sipuleucel-T was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who r equired central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result.