Transcript Immunology at the University of Virginia

Immunology at the
University of Virginia
About me…..
PhD Biochemistry University of Illinois
Postdoc Immunology Harvard University
At UVA since 1980
Professor 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
[email protected]
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 to
practice being relentlessly curious
find out what truly motivates you
There are no stupid questions…….
What do you think of
when you think of …..
Immunology
The Immune Response
The Immune System
So what do you want to know?
Immunology Research at UVA
Immune 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?
What’s all the
excitement about?
Checkpoint blockade inhibitors
Ipilumumab (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
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?
Cellular and molecular players in anti-tumor
immunity
Mellman et al. (2011) Nature. 480: 480-489
Tumor infiltrating lymphocytes predict survival
in colorectal cancer better than Duke’s staging
Galon et al, Science 313 1960 (06)
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 response
Typical for pathogens
Type II inflammatory response
Typical for wound healing
Cancer Immunotherapies
Old and New
Anti-cancer antibodies
Therapeutic vaccines
Adoptive T cell therapy
Checkpoint blockade inhibitors
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
What does the immune system
recognize on tumor cells?
Patient-specific neoantigens
Tissue-specific, cancer-testis
antigens
Phosphopeptides
Phosphopeptides:
a better class of tumor antigen
Cancer Cell
Normal Cell
Overactive
Kinase
Kinase
Proteasome
Inhibited
Phosphatase
Proteasome
Reverse Immunology Approach:
Identify MHC-associated peptides modified by intracellular
phosphorylation using mass spectrometry
Qualify peptides as recognizable by T lymphocytes
Making Better Vaccines
by Targeting the Dendritic Cell
Combining immunotherapies with one another
and with other approaches
Adoptive cell therapy
Chemotherapy
(and radiation)
can induce
“Immunogenic
Cell Death” that
primes the
immune
response
The big picture
Cancer 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
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
Collaboration and Connection
Other UVA Centers of Excellence
Infectious Disease and Biodefense
Host-pathogen interactions
Vaccines and immunotherapeutics
Cancer Biology
Immune regulation in the tumor microenvironment
Vaccines and immunotherapeutics
Inflammation and Vascular Biology
Inflammation (danger) is as important as foreignness
Blood vessels are the immunological highway
Cardiovascular disease is caused by the immune system
Models in Immunology Research
Basic to Clinical
Cell culture - inside and out
Mice – manipulated and otherwise
People – source and subject
Technology – flow cytometry, mass
spectrometry, imaging, genomics, etc
Summer Research
Internship Program
http://www.medicine.virginia.edu/education/phd/g
po/srip/home-page
Biomedical Sciences
Training Program
http://bims.virginia.edu
Immunology Training
Program
http://research.med.virginia.edu/itp/
Immunology Training Program
http://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 Program
Student invited speakers
Anderson and Carter Lectureships
Immunology Training Program
http://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
The graduate experience
Goal: 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
Writing
Papers, grant applications, thesis
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
Making Better Vaccines – Targeting
the Dendritic Cell
Patient cancer
specific
mutations –
tumor
neoantigens –
as the basis for
personalized
immunotherapy
Checkpoint blockade inhibitors release
the brakes on immune responses
T cell targets for immunoregulatory
antibody therapy
I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673
Adoptive T-cell transfer immunotherapy
Treatment of B-cell leukemia using
CAR-T cells
Klebanoff, C. A. et al. (2014) Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2014.190
Chemotherapy and Radiation Work by
Augmenting the Immune Response
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
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
The Immune System
Lymphocytes
Myeloid cells – dendritic cells, macrophages, etc
- How are these cells generated?
How do cells get activated?
How is the expression of different functions
controlled?
How do cells
?
Lymphoid Organs
Antibodies, receptors, cytokines, and chemokines