REQUEST FOR JUNIOR INVESTIGATOR PRE-PROPOSALS COBRE IN IMMUNOLOGY RESEARCH AND IMMUNOTHERAPY IN SOUTH CAROLINA (IRIS)

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Ronald Booker
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1 REQUEST FOR JUNIOR INVESTIGATOR PRE-PROPOSALS COBRE IN IMMUNOLOGY RESEARCH AND IMMUNOTHERAPY IN SOUTH CAROLINA (IRIS) The NIH Centers of Biomedical Research Excellence (COBRE) Program is available to institutions within Institutional Development Award (IDeA)-eligible states, including South Carolina. The objective is to strengthen an institution's biomedical research infrastructure through establishing a thematic, multi-disciplinary center and enhancing the ability of investigators to compete for NIH R01s and similar independent research grants. The key components are strategic scientific cores and research projects led by mentored junior investigators. MUSC will submit a new COBRE application in immunology research and immunotherapy in January The overall PD/PI is Dr. Zihai Li, Chair, Department of Microbiology and Immunology; Dr. Gary Gilkeson, Professor of Medicine/Rheumatology and Associate Dean for Faculty Affairs and Faculty Development in the College of Medicine, is the Associate Program Director. This project received institutional approval last year but was deferred until now because NIH cancelled the January 2015 submission date. This is a request for pre-proposals from eligible junior investigators (JIs) who wish to propose a mentored research project for consideration to be incorporated in the COBRE application. Three slots are available. (Of the initial cadre of five JIs who selected last year, two have achieved grant success and one is leaving MUSC.) A synopsis of the COBRE theme and cores is attached. MUSC s Office of Research Development will coordinate development of the full COBRE application. Eligibility criteria. A junior investigator must have a faculty appointment and must not be (now or at time of submission in January 2016) or previously ever have been the PI of an external, peer-reviewed Research Project Grant (RPG) or Program Project Grant (PPG) from a Federal or non-federal source. MPI status does not disqualify an investigator. Similarly, status as PD/PI of exploratory/pilot project grants (e.g., R03, R21, R15 awards) and/or receipt of mentored career development awards (e.g., K01, K08, K23), or other Federal or non- Federal funding whose purpose is to provide preliminary support in anticipation of a RPG or PPG are not disqualifying events. See for a full description of Criteria for Eligibility of Junior Investigators. Questions regarding eligibility can be directed to Joann Sullivan (sullivan@musc.edu) or Peggy Schachte (schachte@musc.edu). Pre-proposal requirements. the following as a single pdf file to Joann Sullivan, Office of Research Development (sullivan@musc.edu) no later than 5 PM on Monday, August Cover Page containing project title, name and rank of junior investigator PI, and name and rank of proposed primary mentor and additional mentors, if applicable. 2. Narrative not to exceed 3 pages, containing Background, Aims, Approach, Proposed or Potential Use of Cores, and Expertise of Proposed Mentor(s). The 3-pp limit includes figures but references may use additional space. Use Arial 11 font with 0.5 margins on all sides. 3. On a separate page, list all extramurally submitted applications that (a) are pending review and/or (b) have been scored, indicating probability of funding and date of possible award or date of possible resubmission. List only those applications submitted as PI. Provide sponsor and type of mechanism, FOA # if applicable, title, main focus or theme (if not obvious from title) and any overlap with the COBRE pre-proposal. 4. An up-to-date NIH Bio Sketch in the new format. Pre-proposals will be reviewed by the IRIS COBRE Executive Committee with consideration given to: Scientific merit of the proposed research. Candidate s potential for being R01 funded within three years. Fit with COBRE theme of Immunology Research and Immunotherapy and multi-disciplinary relevance. Proposed or potential use of IRIS cores. Candidate s commitment to immunology/immunotherapy research at MUSC. Questions can be directed to Zihai Li (zihai@musc.edu), Gary Gilkeson (gilkeson@musc.edu), Joann Sullivan (sullivan@musc.edu), or Peggy Schachte (schachte@musc.edu).

2 COBRE for Immunology Research and Immunotherapy in South Carolina -IRIS- Medical University of South Carolina, Charleston, SC Overall Program Director/Principal Investigator (PD/PI) Zihai Li, MD, PhD Professor and Chair, Department of Microbiology & Immunology Professor of Medicine, Division of Hematology and Oncology Program Leader in Cancer Immunology, Hollings Cancer Center Associate Program Director Gary Gilkeson, MD Professor of Medicine/Division of Rheumatology & Immunology Associate Dean for Faculty Affairs and Faculty Development, College of Medicine

3 The Vision. An interdisciplinary collaborative biomedical research center that will serve as a driving force for immunology research and immunotherapy at the Medical University of South Carolina and exert collaborative leadership and mentorship in advancing the field of immunotherapy at state, regional and global levels. The Strategy. To create, strengthen and sustain the research infrastructure and core resources required to apply important research discoveries in immunology in the advancement of human health, and to mentor and equip junior investigators to discover underlying novel immunological principles and successfully compete for research program grants from national agencies, including the NIH. Significance of the Theme Summary. The Phase I goal for IRIS is to establish and develop a collaborative, thematic biomedical research center and attain status as a Board of Trustees-approved University Center within five years. Building on significant strengths recently assembled at MUSC as well as strategic commitments aimed at advancing understanding of the host immune system and moving immunotherapy from the bench to the bedside, we will activate three primary approaches to achieve this strategic goal: 1) mentor and equip junior investigators to discover novel immunological principles and become independent federally-funded investigators, 2) create sustainable core resources and other research infrastructure designed to stimulate and apply research discoveries in immunology to the improvement of human health, and 3) attract and retain outstanding basic, translational and clinical scientists who will develop new programmatic initiatives to elucidate immune mechanisms and push the frontiers of immunotherapeutic applications to treat and cure human diseases safely and effectively. We will mentor and support an initial cadre of five junior investigators (JIs). Each JI will submit an R01 grant application after two years of COBRE support as a condition of continuing to receive COBRE support. Once funded as an independent investigator, each JI will graduate and make room for additional JIs, while remaining active members of the COBRE team, retaining access to core resources and career mentoring, and advancing into new roles as emerging mentors and collaborators. The success of these promising JIs will be ensured by a team of outstanding, well-positioned scientist/mentors with demonstrated excellence in their respective fields and proven track records of fostering junior faculty research career development, as well as the strategic support of four vital core resources: Administration & Mentoring (AMC, Core 1), Immune Monitoring & Discovery (IMD, Core 2), Translational Immunology (TIC, Core 3), and Immuno-Informatics (IIC, Core 4). The central features of the mentoring strategy include ongoing constructive, critical evaluation of research projects by mentors, ongoing mentoring and technology updates by core leaders, semiannual mini-conferences on hot topics in immunology research and immunotherapeutics, special training in grant writing, peer review and translational research challenges, and an annual full-day retreat with a blue-ribbon panel of external advisors who are world leaders in immunology and immunotherapy. A strategic, peer-reviewed Pilot Project Program will be initiated in Phase I to attract other junior and established investigators into immunology research and immunotherapy, encourage broad utilization of core resources, and ultimately aid our graduate JIs in strengthening their competitive renewal prospects and developing additional R01 lines of investigation. IRIS and its associated core resources are congruent with the mission and strategic goals of the South Carolina Clinical and Translational Research Institute (SCTR, MUSC s CTSA initiative) and the NCI-designated Hollings Cancer Center (HCC). Therefore, IRIS will benefit significantly from collaborative interactions with both SCTR and HCC to leverage existing research infrastructure and core capabilities in order to strengthen, synergize and enhance immunology research at MUSC without duplicating effort or reinventing the wheel. The fusion of exceptional scientific talent, an outstanding research environment, and substantial institutional commitment to human and translational immunology assures that IRIS will successfully foster the development of a strong immunology-based interdisciplinary research program that enhances the ability of JIs to compete as independent PIs for funding from NIH and other nationally recognized agencies. Rationale. The scientific theme focuses on elucidating fundamental mechanisms of host immune responses in the context of multiple diseases and translating such knowledge to improve human health. Host immune response to diseases is pervasive, and immuno-modulating agents are broadly applicable to the treatment of human diseases, as evidenced by recent explosive growth of new agents in the form of cytokines, antibodies and cell-based therapy for autoimmune diseases, cancer, sepsis and other conditions [1,2,3,4]. With regard to cancer, oncogenic inflammation and evasion from immune surveillance are being recognized as two essential hallmarks in tumorigenesis [5]; therefore, boosting host immune defense against cancer may hold the key to eventual cures [4]. Cancer immunotherapy, considered the 2013

4 Breakthrough of the Year by Science/AAAS [6], is likewise experiencing a true renaissance with promising efficacy against many tumors traditionally thought to be poorly immunogenic, such as lung cancer [7]. Autoimmunity/autoinflammation is another part of the spectrum where biologic therapies have had major impact on patient survival and quality of life. Interestingly, cancer immune therapies can induce autoimmunity in recipients, providing insight into the pathogenesis of autoimmune diseases and opening new crossdisciplinary lines of basic, translational and clinical investigation. Thus, research in immunology has emerged as a strategically critical area in biomedicine and represents a vital research theme that has relevance for all 27 NIH Institutes and Centers. Innovation and Strengths The proposed COBRE embraces multiple areas of innovation while building on strategic strengths, such as: The PD/PI and Associate PD of IRIS, Drs. Li and Gilkeson, are both practicing physician-scientists and leaders in their respective research fields of translational tumor immunology and autoimmunity. IRIS focuses on interdisciplinary human immunology research; each JI proposal will have significant translational potential. The emphasis on immune and inflammatory responses that ubiquitously intertwine with human disease processes will enable IRIS investigators to transect traditional disciplinary boundaries. We believe IRIS will be the only COBRE with a Translational Immunology Core capable of manufacturing clinical grade cellular products to support clinical trials. IRIS will develop a sophisticated human immune monitoring core to accelerate immune-based biomarker discovery. IRIS will create a robust immunology-specific informatics core to support immunology research and immunotherapy, which complements a university-wide effort to boost bioinformatics infrastructure. IRIS will further enhance an already vigorous mentorship program for junior faculty at MUSC enhancing their route to independence and external funding. The trifold purpose of IRIS is to: 1) create sustainable research infrastructure tailored to facilitate human immunology research, 2) apply research discoveries in immunology to advance human health, and 3) mentor and equip junior investigators to discover underlying novel immunological principles and compete for research project grants from the NIH and other federal and non-federal entities. IRIS will have special importance to the people of South Carolina due to the burden of cancer and autoimmune disease in the population we serve. The establishment of IRIS will merge major strengths in cancer immunology and autoimmunity research at MUSC into a collaborative Immunology Research Center. Our Junior Investigators will work together with senior leaders to develop cutting-edge research in immunology that cuts across many disciplines. Aggressive dissemination of the science developed in IRIS will promote the highest likelihood of impacting public health and ultimately establish MUSC as a national leader in immunotherapy of human diseases. Public Health Relevance of Theme Almost all human diseases reflect, at least in part, a response by the host immune system. Full restoration of the host immune defense is increasingly believed to hold the key to curing many human diseases. For example, immune tolerance is regarded as the most critical reason for the still dismal outcome of much cancer care, whereas dysregulation of the immune response contributes to autoimmune diseases and asthma. We lack effective tools for modulating the immune response in ways that impact disease. Cardiovascular disease, the leading cause of mortality in the US, is increasingly thought to have a pathogenic inflammatory component. Inflammation also is recognized as an essential aspect of pathogenesis of metabolic diseases (type 2 diabetes, obesity, osteoporosis), aging and Alzheimer s disease. In addition, with organ and bone marrow transplantation as the established treatment modalities for a variety of diseases, transplantation immunology is an important branch of immunology. Historically, immunologists invented flow cytometry and hybridoma technologies that have revolutionized medicine. Immunologists also discovered the major histocompatibility complex and recognized the importance of personalized medicine a century ago. Thus, the thematic goals of IRIS have farreaching implications for improving human health. Strategic Research Cores Core 1 Administration & Mentoring Core (Core Leader: Zihai Li, MD, PhD). The mission of this core is to oversee the administration of IRIS, mentor JIs, coordinate programmatic efforts in order to optimize resources, and ensure the scientific success and fiscal efficiency of IRIS. The specific goals are to: (a) Organize monthly team meetings; (b) Create and maintain an IRIS website and secure portal for enhanced communications and data sharing and dissemination by the individual projects; (c) Facilitate constructive review of the research progress through Internal and External Advisory Committees; (d) Coordinate annual retreats and symposia; (e)

5 Deliver general administrative and fiscal management support to ensure effective and efficient communication, coordination and compliance with all terms and conditions of the grant, and (f) Initiate a strategic Pilot Project Program to attract other junior and established investigators into immunology research and immunotherapy, encourage use of core resources, and aid our graduate JIs in strengthening their competitive renewal prospects and developing additional R01 lines of investigation. Core 2 Immune Monitoring and Discovery Core (Core Leader: Stephen Tomlinson, PhD; Co-Leader: Chentha Vasu, PhD). Basic immunology research and the development of immunotherapies and vaccines require: 1) sophisticated assessment of immune responses, 2) development of innovative assays to determine the immune responses, and 3) readily available technology, reagents, protocols and know-how for conducting discovery research in an efficient and cost-effective manner. Therefore, the mission of the IMD Core will be to provide comprehensive immuno-monitoring associated services for basic, translational and clinical studies, provide access to cutting-edge technologies at reasonable and sustainable cost, develop innovative immunoassays, and serve as a resource center for standardized protocols, reagents and assay consultancy. The ultimate goal of this core will be to facilitate research discoveries within IRIS and other immunology-related research initiatives of MUSC and South Carolina. This core will include two advanced technologies and services new to MUSC: FlexMap 3D for high throughput analysis of biomolecules (installed and available for use) and CyTOF2 for high density cell phenotyping (requested in an NIH Shared Instrumentation Grant to be reviewed in Fall 2015). In addition, this core intends to arrange favorable terms for JIs and COBRE team members to access standard flow cytometry services through established core resources of HCC. Core 3 Translational Immunology Core (Core Leader: Gary Gilkeson, MD; Co-Leaders: Shikhar Mehrotra, PhD; Xuezhong Yu, PhD; Natalie Sutkowski, PhD; John Zhang, PhD). This core has four components: cellular therapy, humanized mouse technology, human monoclonal antibody technology and mouse monoclonal antibody platform. It will offer IRIS investigators the capacity to generate monoclonal antibodies as well as human cellular and tissue-based products for use in translational research. The mission is to provide an integrated platform to bring immune-based products to patients. The specific objectives are to provide: (a) Expanded cell therapy and gene therapy-based bio-therapeutic products for Phase I and II clinical studies employing current cgmp standards; (b) Regulatory expertise in the preparation of cell- and possibly gene-therapy-based INDs; (c) Consultation and assistance concerning isolation, expansion and scale-up production of T cells, dendritic cells, stem cells or other cell types for translational studies; (d) Full-service production of mouse monoclonal antibodies to IRIS investigators at a cost substantially lower than that of commercial vendors; (e) Access to a novel human monoclonal antibody production platform; and (f) Expertise in establishing human hematopoietic system in immunocompromised mice for translational research. Core 4 Immuno-Informatics Core (Core Leader: Gerard Hardiman, PhD; Co-Leader: Elizabeth Hill, PhD). In collaboration with HCC, SCTR, the Dept. of Public Health Sciences and the Provost s Office, IRIS will establish a novel Immuno-Informatics Core to enable MUSC investigators to capitalize on the explosive growth of Big Data in immunology in areas such as: (a) high-performance computing infrastructure, Big Data management via an immunomic database; (b) reverse vaccinology and epitope prediction for immunology research; (c) microbiomics in the context of host defense; (d) integrative biostatistics and immuno-systems biology; (e) immunoregulatory gene association studies; and (f) mentoring in bioinformatics and biostatistics. This core differs from traditional informatics cores as it focuses on immunology, requiring core leaders to be proficient in both informatics and immunology. Anticipated Impact and Potential Value the New COBRE Will Bring to MUSC IRIS s impact at MUSC will be immediate and transformational, including but not limited to: (i) Establishing MUSC as a national leader in immunology research and immunotherapy; (ii) Creating a state-of-the-art facility in human immune monitoring; (iii) Strengthening a key research program in HCC (i.e., Cancer Immunology) to ensure continuing NCI designation and enhance prospects for attaining comprehensive status in 2018; and (iv) Expanding SCTR capabilities in translational research and helping ensure its continuous NIH funding. References Cited [1] R. M. Steinman, I. Mellman, Immunotherapy: bewitched, bothered, and bewildered no more, Science 305 (2004) [2] L. Steinman, Immune therapy for autoimmune diseases, Science 305 (2004) [3] A. M. Scott, J.D. Wolchok, L.J. Old, Antibody therapy of cancer, Nat Rev Cancer 12 (2012) [4] Z. Li, L. Chen, M. P. Rubinstein, Cancer immunotherapy: are we there yet?, Exp Hematol Oncol 2 (2013) 33. [5] D. Hanahan, R. A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) [6] M. McNutt, Cancer immunotherapy, Science 342 (2013) [7] S. L. Topalian, F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith et al, Safety, activity, and immune correlates of anti-pd-1 antibody in cancer, N Engl J Med 366 (2012)

2016 San Antonio Claude D. Pepper Older Americans Independence Center Pilot and Exploratory Study Core REQUEST FOR APPLICATIONS PILOT PROJECTS

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