Immunology at the University of Virginia. About me….. PhD Biochemistry University of Illinois Postdoc Immunology Harvard University At UVA since 1980.

Immunology at the University of Virginia

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

[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 topractice 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 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?

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

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 responseTypical for pathogens

Type II inflammatory responseTypical for wound healing

Cancer ImmunotherapiesOld 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

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

Making Better Vaccinesby 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 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

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 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

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

Summer Research Internship Program

http://www.medicine.virginia.edu/education/phd/gpo/srip/home-page

Biomedical Sciences Training Program

http://bims.virginia.edu

Immunology Training Program

http://research.med.virginia.edu/itp/

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

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

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

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

I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673

T cell targets for immunoregulatory antibody therapy

Adoptive T-cell transfer immunotherapy

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

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 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