The (Internal) War on Using the to Fight Tumors

Jernej Godec, Harvard Medical School and DFCI Ezana Demissie, Massachusetts General Hospital Vikram Juneja, Harvard Medical School and MIT

Dr. William Coley (1862-1936) Roadmap for the evening

1. Introduction to cancer and the immune system Jernej

2. Twists & turns in the story of Ezana

3. Therapeutic breakthroughs in cancer immunology Vikram What is cancer? Uncontrolled expansion of abnormal cells

Accumulation of mutations Immune system is complex with many players having specific roles

T cell B cell

Natural killer Dendritic cell Macrophage Neutrophil cell Immune system has evolved to fight foreign invaders Dendritic Cell recognizes T cells eliminate virus- invaders and gets alarmed producing cells and restore balance

The correct T cell built to fight this invader is found and activated Each of the ~10,000,000,000 T cells has one T cell receptor (TCR) that recognizes one molecule

T cell progenitor

Naive T cell T cell activation is a tightly regulated series of events

Alarmed dendritic Naive T Army of activated cell bringing foreign cells killer cells molecules T cell activation is a tightly regulated series of events

CD28 TCR PD-1 CTLA-4 B7 SLOW PD-L1

TCR = T cell receptor Questions? In a similar fashion, the immune system also protects us from cancer Dendritic cell eventually Activated T cells to the tumor recognizes tumor cells and to eliminate cancer cells gets alarmed

T cell is activated by the dendritic cell and multiplies Tumors have evolved ways to evade the immune system

Tumor cells hijack Tumor cells change Tumor cells too similar inhibitory mechanism the molecules that let to healthy cells and prevent T cell killing T cell identify them

? ? ? ? ? ? SLOW PD-L1 SLOW Questions? Roadmap for the evening

1. Introduction to cancer and the immune system Jernej

2. Twists & turns in the story of cancer immunotherapy Ezana

3. Therapeutic breakthroughs in cancer immunology Vikram The legacy of Bessie Dashiell

- John D. Rockefeller Jr.’s teenage friend

- Death inspires William Coley

Dr. William Coley (1862-1936)

Gibson Girls seaside -cropped- by Charles Dana GibsonPublic Domain Coley’s toxin

- Finds patient cured of cancer following post-op bacterial infection - Concocts Coley’s toxin Live & heat killed bacteria to treat cancer Loses out to chemo/radiation

Dr. William Coley (1862-1936) - Father of Cancer Immunotherapy “The day will yet come when posterity will be amazed that we remain so ignorant of things that will seem to them so plain”

- Seneca, quoted by William Coley in “The idea of Progress”, 1920 Immune system has Immune system has a protective role no protective role in cancer in cancer Hypothesis 1: Immune system has no protective role in cancer Tumor-promoting immune responses Normal Liver

Chronic Infection Formation of Scar Tissue Liver Chronic Cancer Immune Responses Hypothesis 1: Immune system has no protective role in cancer

Nude Mouse - Discovered by farmer - Spontaneous mutation

- No T-cells

Kuebi = Armin Kübelbeck - Own work Immune system has Immune system has a protective role no protective role in cancer in cancer • Tumor-promoting inflammation • No increase in Nude mouse cancer rates Hypothesis 2: Immune system has a protective role in cancer

B cell Natural killer T cell cell

Dendritic cell Macrophage Neutrophil Hypothesis 2: Immune system has a protective role in cancer

Normal mouse

Immunodeficient Mouse No Tumors Intermediate Advanced

Shankaran, V. et al. IFN[gamma] and lymphocytes prevent primary tumour development and shape tumour immunogenicity : Article : Nature. Nature 410, 1107–1111 (2001). Hypothesis 2: Immune system has a protective role in cancer

Intratumoral T cells No intratumoral T cells Hypothesis 2: Immune system has a protective role in cancer Intratumoral T cells No intratumoral T cells

Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New England Journal of 348, 203–213 (2003) Immune system has Immune system has a protective role no protective role in cancer in cancer • Nude mice not completely • Tumor-promoting inflammation immunodeficient • No increase in Nude mouse • Severely immunodeficient mice cancer rates have higher spontaneous cancer incidence • Patients with intratumoral T cells have significantly better prognosis

Questions? PART II

How does the immune system recognize tumors? – Tumor Antigens How are excessive immune responses kept in check? – Checkpoints in immune activation Tumor Antigens (What does the immune system see?)

Inject “weakened” red Challenge mice with “Weaken” red tumors tumors Result red and green tumors into mice

Red tumor rejected

Green tumor grows

à There is a specific response against the tumor à The immune system can distinguish normal cells from cancerous cells HOW? Accumulation of mutations (What does the immune system see?) system see?) the immune (What does Tumor Antigens Tumor Antigens

Production of Tumor Antigens à à à Causes: Genomic Instability

(germ line vs. adult tissues) vs.tissues) adult line (germ to be not supposed they are proteins Expression of proteins where where of proteins Expression of proteins Over production new that produce Mutations

Checkpoints in immune activation

Hiro Sheridan Attribution 2.0 Generic

SLOW

Loss of CTLA-4 Fatal Tumor Autoimmunity Clearance Normal Mice Normal Mice CTLA-4 PERMANENT loss CTLA-4 TEMP loss %Survival

Time Leach, D. R., Krummel, M. F. & Tivol, E. A. et al. Loss of CTLA-4 leads to massive Allison, J. P. Enhancement of lymphoproliferation and fatal multiorgan tissue antitumor immunity by CTLA-4 destruction, revealing a critical negative regulatory blockade. Science 271, 1734– role of CTLA-4. Immunity 3, 541–547 (1995). 1736 (1996).

SLOW Loss of PD-1

NO spontaneous autoimmunity Normal mouse

CTLA-4 deficient PD-1 deficient

SLOW

SLOW Loss of PD-1 Key during chronic infections

Chronic Viral Infection

Normal Mice PD-1 deficient

SLOW PD-1LOSS

Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006). Tumors have evolved ways to evade the immune system

Tumor cells hijack inhibitory mechanisms

SLOW In a nutshell…… 1. The immune system plays a key role in tumor surveillance

2. Tumors express antigens that allow recognition by the immune system

3. The immune system uses several checkpoints ensuring an appropriate response

Lab bench to bedside in 20+ years

SLOW

2011 2000 FDA 2014 Human Approval 2006 FDA 1997 Patients Human Approval Treat 2002 Patients Treat 1995 mouse tumors 1999 mouse Gene tumors deficient Gene mice deficient 1987 1993 mice Gene Gene identified identified BASIC RESEARCH BASIC RESEARCH Roadmap for the evening

1. Introduction to cancer and the immune system Jernej

2. Twists & turns in the story of cancer immunotherapy Ezana

3. Therapeutic breakthroughs in cancer immunology Vikram The immune system responds to cancer

? ? ?? ? ? Using the immune system to fight cancer

Two general approaches

1. Take immune cells out of body à Manipulate them à Put them back in

2. Manipulate immune cells while still in patient

2 general approaches to immunotherapy 1) Take cells out of body à Manipulate them à Put them back in 2 general approaches to immunotherapy 2) Manipulate immune cells while still in patient Using the immune system to fight cancer

Two general approaches

1. Take immune cells out of body à Manipulate them à Put them back in

2. Manipulate immune cells while still in patient A Success Story: Emily Whitehead • Diagnosed with Acute Lymphoid Leukemia at 5 years old – Chemotherapy à declared in remission • Cancer cells detected 17 months later – Chemotherapy à declared in remission • Cancer cells detected 4 months later – Chemotherapy à no response • Doctors took out her T cells, engineered them to attack the tumor cells, and put them back in – Declared in remission after 1 month* – Cancer free today (>2 years) http://emilywhitehead.com/ Adoptive cell transfer Chimeric Antigen Receptors (CARs) 2nd and 3rd Generation CARs Lessons learned from clinical trials

• 14 published trials, >20 ongoing – Primarily looking at blood – Many respond within a month, though different cancers clearly respond differently • Too early to make a call on long-term effects – Some patients have relapsed • Main side effects: “Cytokine Release Syndrome” – Excessive immune response Questions? Using the immune system to fight cancer

Two general approaches

1. Take immune cells out of body à Manipulate them à Put them back in

2. Manipulate immune cells while still in patient The goal of checkpoint blockade CTLA-4 blockade in the clinic

Control Few patients, CTLA-4 but durable blockade response CTLA-4 blockade + control

Hodi, F. S. et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363, 711–723 (2010). Point of comparison

Many patients, but short-term response Targeted therapy (N=336) Few patients,

but durable Chemotherapy response (N=336)

Hodi, F. S. et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363, 711– 723 (2010). Chapman, P. B. et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl J Med 364, 2507–2516 (2011). Lessons learned from this clinical trial Many other signals are being studied

D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy.,” Nat. Rev. Cancer, 12(4): 252–264 (2012). PD-1 has emerged as a leading contender

SLOW

Hiro Sheridan Attribution 2.0 Generic SLOW PD-1 blockade in the clinic

Topalian, S. L. et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med 366, 2443–2454 (2012). So where do we go from here?

• Discovery of new targets

• Combining therapies – Immunotherapy + immunotherapy – Non-immunotherapy + immunotherapy

• “Personalized medicine” – Choosing which immunotherapy will work for each patient Combining CTLA-4 with PD-1 blockade

Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369, 122–133 (2013). Other therapies that affect the immune response

• Other immunotherapies already in the clinic – Dendritic cell vaccines – Cytokine therapy

• Conventional therapies also affect the immune response – Chemotherapy – Targeted therapy Takeaway points • The immune system attempts to clear cancer cells when they form

• When patients come to clinic, this implies the immune response has effectively failed

• New therapies are emerging that aim to help the immune system or induce a new response Thank you, Sydney! Thank you, Emily and family!

www.emilywhitehead.com Thank you! SITN would like to acknowledge the following organizations for their generous support.

Harvard Medical School Office of Communications and External Relations Division of Medical Sciences

The Harvard Graduate School of Arts and Sciences (GSAS)

The Harvard Graduate Student Council (GSC)

The Harvard Biomedical Graduate Students Organization (BGSO)

The Harvard/MIT COOP