PROJECT SUMMARY IMMUNO-ONCOLOGY PROGRAM The overarching goal of the Immuno-Oncology Program (IO) is to develop, mechanistically understand and deliver effective and safe immunotherapies for cancer patients, with a focus on cancers that disproportionately affect patients in our catchment area. Key to success of the IO Program is the integration and synergy of basic and translational immunologists with clinicians implementing clinical trials through an interdisciplinary, “bench- to-bed-and-back” continuum. Moffitt has become a leader in state-of-the-art immunotherapy trials and to build upon this success, the research activities of IO are organized into three Specific Aims: Aim 1: To understand molecular and cellular mechanisms that exploit innate and adaptive immunity against cancer. Specific areas of focus include: 1) dissecting novel immune checkpoint inhibitory pathways and their crosstalk with other immunosuppressive mechanisms; 2) understanding coordinated cellular and humoral responses against cancer; and 3) defining metabolic alterations in innate and adaptive immune cells. Aim 2: To elucidate and target pathways governing effectiveness, resistance, and toxicity in anti- cancer immunotherapy. Specific areas of focus are: 1) providing biological and clinical insights into how to augment responses to immune checkpoint inhibitors; 2) identifying actionable epigenetic mechanisms that govern malignant progression and the effectiveness of immunotherapies; and 3) improving the effectiveness of bone marrow transplant while reducing graft versus host disease. Aim 3: To develop and implement anti-cancer cellular therapies. Specific areas of focus include targeting high priority cancers in our catchment area (e.g., melanoma, lung, cervical and ovarian cancer) by: 1) developing, implementing and refining CAR T cell therapies against human cancers, including solid malignancies; and 2) effectively treating cancer through ex vivo expanded tumor-infiltrating lymphocytes (TILs). IO has made huge impact in immuno-oncology, where IO Members have: 1) led efforts resulting in FDA approval of CAR T cells for treatment of refractory B cell lymphoma; 2) pioneered the use of TILs to achieve therapeutic responses in melanoma, and in chemo- and immunotherapy-resistant lung cancer; 3) discovered a novel targetable checkpoint inhibitory pathway in human cancer; and 4) driven changes in clinical management of CAR T and checkpoint inhibitor patients. Publications during this cycle include 136 manuscripts in journals with IF ³ 10, including NEJM, Science, Nature, Lancet Oncology, Cancer Cell and Immunity, among others. IO is comprised of 36 Members from 9 academic departments. During the reporting period, 648 cancer-related articles were published, with 21% intra-programmatic and 46% inter-programmatic collaboration rates. Current grant funding for IO is $19.3 million, of which $6.8 million is peer-reviewed, including 37% from NCI (a 36.6% increase compared to the previou...