6 2.0 TRIAL DESIGN ........................................................................................................... 7 2.1 Trial Design .............................................................................................................. 7 2.2 Trial Diagram ............................................................................................................ 7 3.0 OBJECTIVES & HYPOTHESES ................................................................................ 7 General Scientific Hypothesis ……………………………………………………...7 3.1 Primary Objectives & Hypotheses ............................................................................ 8 3.2 Secondary Objectives & Hypotheses ........................................................................ 8 4.0 BACKGROUND & RATIONALE .............................................................................. 8 4.1 Background/Introduction .......................................................................................... 8 4.1.1 Overview of Small Cell Lung cancer .................................................................... 8 4.1.2 p53 as a Target for Cancer Immunotherapy .......................................................... 8 4.1.3 Anti-p53 Dendritic Cell Based Immunotherapy………………………………9 4.2 Vaccine (Ad.p53 -DC) Immunotherapy .................................................................... 9 4.2.1 Manufacturing of Ad.p53- DC ............................................................................... 9 4.2.2 Preclinical Animal Studies with Ad.p53 -DC ...................................................... 10 4.2.3 Preclinical Experiments Using Human T cells ................................................... 11 4.3 Phase I/II Clinical Trial of Ad.p53- DC in SCLC ................................................... 11 4.3.1 Study Design and Patient Characteristics .......................................................... 11 4.3.2 Ad.p53- DC Dose and Safety .............................................................................. 12 4.3.3 Immune Response to Ad.p53- DC ...................................................................... 12 4.3.4 Cl inical Efficacy of Ad.p53- DC and Enhanced Effect on Salvage Chemotherapy …………………………………………………………………………..13 4.4 Improved Ad.p53-DC Immunotherapy Strategy………………………………….13 4.4.1 Role of MDSCs in the Immune Response………………………………………13 4.4.2 Rationale for the Use of ATRA in Combination with Ad.p53- DC……………..14 4.4.3 Randomized Phase II Clinical Trial in SCLC …………………………………..14 4.5 Checkpoint Inhibitors Immunotherapy …………………………………………...18 4.5.1 Nivolumab……………………………………………………………………....18 4.5.2 I pilimumab……… …...…………………….…………………………………...19 4.6 Study Rationale…………………………………………………………………...19 4.6.1 Rationale for Immuno-Oncology Therapeutic Approaches in SCLC…………19 4.6.2 Rationale for Nivolumab/Ipilimumab Combination in SCLC …………………..20 4.6.3 Rationale for the Use of ipi-Nivo in Combination with Ad.p53- DC…………21 5.0 METHODOLOGY ..................................................................................................... 22 5.1 Entry Criteria ..........................................................................................................