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Immunology at the University of Virginia
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About me…..PhD Biochemistry University of Illinois
Postdoc Immunology Harvard University
At UVA since 1980Professor of Microbiology, Immunology, and Cancer Biology
Director, Carter Immunology Center
Co-Leader, Cancer Immunology and Immunotherapy Program, UVA Cancer Center
Director, Immunology Training Program
Trained 32 PhD graduate students, 27 postdoc fellows
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Doing science – graduate school and beyond
Curiosity – what do you want to know?
Motivation – what drives/focuses your curiosity?
The best graduate training gives you a chance topractice being relentlessly curious
find out what truly motivates you
There are no stupid questions…….
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What do you think of when you think of …..
Immunology
The Immune Response
The Immune System
So what do you want to know?
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Immunology Research at UVAImmune System Function and Dysfunction
What kinds of immune responses are necessary to control bacteria, viruses, parasites, and tumors?
How can they be regulated and improved?
How can we make better vaccines for malaria, tuberculosis, and cancer?
How do autoimmune diseases develop?
How is self-tolerance established and maintained?
What kinds of immune responses cause allergies?
Why do allergic responses develop against innocuous substances?
What’s the basis for immune deficiencies, leukemias, lymphomas?
What processes control the development of lymphocytes?
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What’s all the excitement about?
Checkpoint blockade inhibitorsIpilumumab (Yervoy) – 10-20% overall response rate in melanoma
Pembrolizumab (Keytruda) and nivolumumab (Opdivo) – 30-40% overall response rate in melanoma; 20-30% in lung, renal cancers, mesothelioma, TN breast cancer
Combination greater that 80% tumor shrinkage in 30% of melanoma patients
CAR-T - >80% response in B cell leukemias
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Being curious about the immune response to cancer
Is there an immune response to cancer?
What does the immune system recognize on cancer cells?
What kind of immune response is needed to control or cure cancer?
How do we improve that immune response in cancer patients?
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Cellular and molecular players in anti-tumor immunity
Mellman et al. (2011) Nature. 480: 480-489
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Tumor infiltrating lymphocytes predict survival in colorectal cancer better than Duke’s staging
Galon et al, Science 313 1960 (06)
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Why do induced specific immune responses fail to control tumors?
• Minimal infiltration of immune cells• Immunosuppressive microenvironment with similarities to
“wound healing”• Adaptation based on a “persistent pathogen”
Acute inflammatory responseTypical for pathogens
Type II inflammatory responseTypical for wound healing
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Cancer ImmunotherapiesOld and New
Anti-cancer antibodies
Therapeutic vaccines
Adoptive T cell therapy
Checkpoint blockade inhibitors
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Cancer vaccines
Therapeutic, not prophylactic – treating people who already have a disease
Stimulate an already developed but suboptimal or moribund response
Stimulate a new response not already induced by the tumor
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What does the immune system recognize on tumor cells?
Patient-specific neoantigens Tissue-specific, cancer-testis antigens
Phosphopeptides
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Kinase
Proteasome
Normal Cell
Overactive Kinase
Proteasome
Cancer Cell
Phosphopeptides: a better class of tumor antigen
Reverse Immunology Approach: Identify MHC-associated peptides modified by intracellular phosphorylation using mass spectrometry
Qualify peptides as recognizable by T lymphocytes
InhibitedPhosphatase
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Making Better Vaccinesby Targeting the Dendritic Cell
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Combining immunotherapies with one another and with other approaches
Adoptive cell therapy
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Chemotherapy (and radiation)
can induce “Immunogenic
Cell Death” that primes the
immune response
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The big pictureCancer immunotherapy approaches are based on discoveries by scientists who were not necessarily interested in either cancer or immunology
Immunotherapies are only effective for certain kinds of cancer, and then only in a subset of patients – why?
Understanding how to regulate the immune response to cancer also creates opportunities to regulate other kinds of immune responses – pathogens, autoimmunity, and allergy
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Immunology Centers and Programs at UVA
Department of Microbiology, Immunology, and Cancer Biology
Carter Immunology Center
Center for Immunology, Inflammation and Regenerative Medicine
Immunology and Immunotherapy Program of the UVA Cancer Center
Activities and funds to support research
Increased breadth of immunologically-related activities
Networking and collaboration
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Collaboration and ConnectionOther UVA Centers of Excellence
Infectious Disease and BiodefenseHost-pathogen interactions
Vaccines and immunotherapeutics
Cancer BiologyImmune regulation in the tumor microenvironment
Vaccines and immunotherapeutics
Inflammation and Vascular BiologyInflammation (danger) is as important as foreignness
Blood vessels are the immunological highway
Cardiovascular disease is caused by the immune system
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Models in Immunology ResearchBasic to Clinical
Cell culture - inside and out
Mice – manipulated and otherwise
People – source and subject
Technology – flow cytometry, mass spectrometry, imaging, genomics, etc
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Summer Research Internship Program
http://www.medicine.virginia.edu/education/phd/gpo/srip/home-page
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Biomedical Sciences Training Program
http://bims.virginia.edu
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Immunology Training Program
http://research.med.virginia.edu/itp/
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Immunology Training Programhttp://research.med.virginia.edu/itp/
31 mentors
NIH sponsored training grant
Stipend/tuition for 2nd, 3rd year students
Specialized coursework in Immunology
Research in Progress Series
Immunology Seminar ProgramStudent invited speakers
Anderson and Carter Lectureships
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Immunology Training Programhttp://research.med.virginia.edu/itp/
Year 1
BIMS or MSTP coursework and lab rotations
Choose mentor
Two Fundamental Immunology modules in spring
Year 2
Two Advanced Topic Modules in Fall
Writing course in Fall
Qualifying Exam in Spring
Year 3
1 Advanced Topic Module
All years
Research-In-Progress
Student run summer journal club
RESEARCH
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The graduate experienceGoal: To prepare you to be among the next generation of biomedical researchers
Bench Research: How to formulate a hypothesis you can test
How to design, conduct, interpret a well-controlled experiment
How to do it again – developing a line of investigation
Oral Presentations Journal clubs, Research presentations, lab meetings
Organizing your thoughts, anticipating questions, thinking on your feet, teaching
WritingPapers, grant applications, thesis
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Why Immunology at UVA?Outstanding science
First class technical facilities
Opportunities from basic to clinical
Strong support for graduate student development
Collaborative and collegial environment
Success in future career – academia, biotech, big pharma, and others
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Making Better Vaccines – Targeting the Dendritic Cell
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Patient cancer specific
mutations – tumor
neoantigens – as the basis for
personalized immunotherapy
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Checkpoint blockade inhibitors release the brakes on immune responses
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I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673
T cell targets for immunoregulatory antibody therapy
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Adoptive T-cell transfer immunotherapy
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Klebanoff, C. A. et al. (2014) Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2014.190
Treatment of B cell leukemia using ‑CAR-T cells
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Chemotherapy and Radiation Work by Augmenting the Immune Response
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Where do we go from here?
The majority of patients with melanoma, lung cancer, and renal cancer do not respond to checkpoint blockade inhibitors
Responses are correlated with mutation load and presence of T cells in the tumor before treatment
Responses in patients with prostate, breast, colorectal, and pancreatic cancers are very low
The microenvironments of these tumors may activate distinct immunosuppressive pathways
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Where do we go from here?
CAR-T and TIL therapies are effective in the majority of B-cell leukemia and melanoma patients
Expansion of these approaches is limited by:Identification of appropriate antigens
Understanding how to improve T cell entry into tumors
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The Immune SystemLymphocytes
Myeloid cells – dendritic cells, macrophages, etc
Development - How are these cells generated?
Differentiation How do cells get activated?
How is the expression of different functions controlled?
How do cells communicate and collaborate?Lymphoid Organs
Antibodies, receptors, cytokines, and chemokines