Conflict of Interest GlaxoSmithKline Pharmaceuticals Board of - - PowerPoint PPT Presentation

Conflict of Interest

• GlaxoSmithKline Pharmaceuticals Board of Directors
• Waters Corporation Board of Directors
• Former Director Bristol-Myers Squibb
• Quentis, Inc Founder and Chair of Scientific Advisory

Board (private)

• Abro Therapeutics Scientific Advisory Board (private)
• Repare Therapeutics Scientific Advisory Board (private)

LHG holds equity in all of these companies

National Academy of Medicine October 15th, 2018

Laurie H. Glimcher, M.D. Dana Farber Cancer Institute Harvard Medical School

Cancer Immunotherapy : The End of the Beginning

Conflicts of Interest

• Board of Directors, GlaxoSmithKline Co. and

Waters Corporation

• Founder, Quentis Therapeutics
• Board of Directors Bristol-Myers Squibb 1997-

2016

3

Setting the Stage

This is the most exciting time in history for cancer research and care

The need is pressing:

• High incidence with 1.7M new cases annually in US
• Cancer is the leading cause of death for ages 45 – 64
• Second-highest cause for 65+ (after cardiovascular)
• Two out of five Americans will develop cancer
• Proportion of US population dying of cancer has not

changed since 1960 likely due to longer life-span

Source: CDC 10 Leading Causes of Death by Age Group, United States - 2015

Cancer Incidence and Survival Today

Some cancers have excellent outcomes, but there is still great progress to be made

4

Cancer Types by Incidence and Survival

1

5-Year Survival1 Incidence per 100,000

Size of Bubble: % of Cancer Deaths

5

Setting the Stage This is the most exciting time in history for cancer research and care

The need is pressing:

• High incidence with 1.7M new cases annually in US
• Cancer is the leading cause of death for ages 45 – 64
• Second-highest cause for 65+ (after cardiovascular)
• Two out of five Americans will develop cancer

Source: CDC 10 Leading Causes of Death by Age Group, United States - 2015

6

Key innovations in cancer treatment

• Epigenetics: Reprogramming cancer cells to normal behavior
• Prevention & Early Detection: Understanding cancer genesis
• Immuno-Oncology: Activating the immune system
• Cancer Genomics: Next generation targeted therapies

Cancer Genomics: Dana-Farber/ BWH PROFILE test

• 400+ cancer genes
• Tested systematically by genome sequencing and

computational analysis

• 28,000+ cancer patients
• Every cancer patient at Dana-Farber gets genomic testing
• Thus each patient has the opportunity to get targeted

therapy if it is appropriate

Cancer Incidence Today

Some cancers have excellent outcomes, but there is still enormous progress to be made

7

Cancer Types by Incidence and Survival

1

5-Year Survival1 Incidence per 100,000

Size of Bubble: % of Cancer Deaths

Cancer Incidence Today

Targeted therapy benefits patients with genomic mutations and has little toxicity

Survival of lung cancer patients treated with osimertinib (Drug developed thanks to research by Dana-Farber scientists)

With mutation Without mutation

September 2011 April 2017

• ALK inhibitor, crizotinib (DF/HCC trial 09-303)
• Patient has been cancer-free for 7 years

Source: DFCI, Office of the Chief Clinical Research Officer

8

Targeted Therapy successful for many patients Targeted Therapy successful for many patients

12

Only the Tip of the Iceberg

• Many patients treated with targeted therapy

have remarkable results and extended life span but,

• Most patients treated with targeted therapy

eventually relapse because the tumor develops additional genetic mutations

• We need combination therapy and what

else?

www.livescience.com

Cancer cell

T cells

Cancer Immunotherapy

“Harnessing the power of the immune system to eliminate tumors”

T cell infiltration into tumors correlates with prognosis

NEJM Jan 16, 2003 348; 203-13

CD3+ TILs

A Little History: Coley’s Toxins

• Dr. William Coley 1893

Effective Immunotherapies

13

Cancer immunotherapies fall into four main buckets Cancer Vaccines Adoptive T Cell Therapy Checkpoint Blockade Tumor micro- Environment

Waking up xxhausted killer T cells with checkpoint blockade

• Dr. James Allison 2018 Nobel Laureate
• Killer immune T cells are exhausted because of inhibitory surface

molecules

• Blocking those surface molecules activates the immune system
• Ipilimumab: Blocks CTLA-4; successful in melanoma- some durable

remissions

Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab Successful in melanoma, squamous/non-squamous lung, kidney, head and neck cancers, bladder, Hodgkins lymphoma, liver, Merkel cell, MSIhi and gastroesophageal cancer

Checkpoint Blockade

More Checkpoint Blockade

Inhiibtory antibodies against PD1/PDL1

• Dr. Gordon Freeman Dana-

Farber Cancer Institute

• Dr. Tasuku Honjo

Kyoto University

• Dr. Lieping Chen

Yale University

The Big “But….”

Breakthrough immunotherapies still only help a minority of patients and a minority of tumor types

Example: Melanoma Tumor Response Rate

40% 24% 11% 60% 76% 89% 0% 20% 40% 60% 80% 100% PD-1 + CTLA-4 PD-1 CTLA-4

Response Non-Response

Immune Responsive Tumors Today:

Melanoma, Lung, Kidney, Bladder, Hodgkin’s Disease, Head & Neck, Liver, GES, MSIHicolon

Yervoy (CTLA-4) Keytruda (PD1) Opdivo + Yervoy (PD1 + CTLA-4) Treatments

24

CAR-T Cells “A Living Drug”

• Doctors remove T cells from a patient
• Genetically engineer them to recognize and “super kill”

the tumor

• Manufacture large numbers of them
• Reinfuse them back into patient

Works for some blood cancers but can be highly toxic Expensive because personalized for each patient and manufacturing costs

A vaccine for melanoma developed and first in human clinical trial done at DFCI

Cathy Wu MD PhD

Effective Immunotherapies

19

Cancer immunotherapies fall into four main buckets Cancer Vaccines Adoptive T Cell Therapy Checkpoint Blockade Tumor micro- Environment

Current immunotherapies fail partly due to a highly immunosuppressive tumor microenvironment (TME)

Myeloid-derived suppressor cell (MDSC) accumulation Prostaglandins T cell exhaustion Inhibitory checkpoints Regulatory T cells (T-regs) Immunosuppressive cytokines T cell exclusion Dendritic cell (DC) dysfunction

Targeting the endoplasmic reticulum stress (ER stress) response can comprehensively reprogram a hostile tumor microenvironment

• A signal transduction pathway from the ER to the nucleus that

protects cells from stress caused by unfolded or misfolded proteins, nutrient deprivation, hypoxia, reactive oxygen species

• Driven by three ER stress sensors resident in ER membrane
• Most evolutionarily conserved is IRE1 whose downstream

substrate is transcription factor XBP1

Liou, Glimcher, Science (1990) Reimold, Glimcher, Nature (2000) Yoshida et al., Cell (2001) Shen et al., Cell (2001) Calfon et al., Nature (2002)

The Unfolded Protein (UPR) or Endoplasmic Reticulum (ER) Stress Response

There are multiple sources of ER stress in the tumor and in the tumor microenvironment (TME)

Hypoxia Nutrient deprivation pH stress ROS

ER stress

Hostile environment Chemo/radiotherapy Genetic alterations High metabolic demand

Hypoxia Nutrient deprivation pH stress ROS

ER stress

Hostile environment Chemo/radiotherapy Genetic alterations High metabolic demand

Protein folding Protein degradation Translation Secretion Apoptosis UPR ATF6 IRE1a PERK

The Unfolded Protein Response (UPR) is triggered to correct this local ER stress

ER lumen Cytosol

Chaperones Foldases ERAD Quality control ER expansion Autophagy

Schroder et al., Annual Review Biochem 2005 Hetz et al., Molecular Cell 2009 Rojas-Rivera D. Adv Exp Med Biol 687; 33-47. 2010

The IRE-1/XBP-1 Signaling Pathway

IRE-1 Accumulation of misfolded proteins Hypoxia,nutrient deprivation

Nucleus

XBP1s

IRE1 endonuclease cleaves its substrate: Converts XBP1 unspliced to XBP1 spliced

Kinase domain Endoribonuclease domain

IRE1/XBP1 in ovarian cancer: targeting the immune system tumor microenvironment

ER Stress in Cancer

IRE1a/XBP1 signaling directly promotes dendritic cell dysfunction

Juan Cubillos-Ruiz Cell, 2015

Ovarian Cancer (OvCa)

1 in 95 women will die of ovarian cancer

Most lethal gynecologic cancer and the 5th most frequent cause of cancer deaths in women

Current treatments show poor success

(surgery and chemotherapy but PARP inhibitors now available)

Overall survival rate: ~40% High recurrence rate due to multidrug resistance

1975-77 1987-89 2002-2008

20 40 60 80 100

Survival rate (%)

Ovarian cancer 5-year survival rates

Dysfunctional Dendritic Cells are Key Mediators of Immune Suppression in the Ovarian Cancer Microenvironment

T cell Dendritic cell (DC)

• Release pro-angiogenic factors
• Promote tumor growth
• Express immunosuppressive

molecules

• Unable to present antigens to T

cells

• Don’t support T cell function

Huarte, Cubillos-Ruiz and Conejo-Garcia. Cancer Res. 2008 Conejo-Garcia and Coukos. Nature Med. 2004 Cubillos-Ruiz and Conejo-Garcia. Cancer Res. 2012 Scarlett, Cubillos-Ruiz and Conejo-Garcia. J Exp Med. 2012 Cubillos-Ruiz and Conejo-Garcia. J. Clin. Invest. 2009 Cubillos-Ruiz and Glimcher. Cell. 2015

Immunosuppressive DCs are the “brakes” in ovarian cancer

Does ER Stress in dendritic cells contribute to a hostile tumor microenvironment?

• rs

C B

20 30 40 50 200 400 600 800

XBP1f/f XBP1f/f CD11c-cre

* ** ** ** ** *

days post ADV-Cre Tumor volume (mm3)

ses

XBP1f/f

A B

XBP1f/f CD11c-Cre

Cubillos-Ruiz et al. Cell, 2015

IRE1 or XBP1 Deletion in Dendritic Cells Impairs the Development and Growth of Primary Ovarian Tumors

P53-/-KRAS-driven model of Ovarian Cancer Scarlett, JEM 2012

IRE1 or XBP1 Ablation in DCs Hinders Metastatic Ovarian Cancer Progression

Cubillos-Ruiz et al. Cell, 2015

E

F

G

Abrogating IRE1α/XBP1 Signaling in Dendritic Cells Restores Their Function in the Tumor Microenvironment

T cell Dendritic cell (DC)

IRE1/XBP1-deficient tDCs:

• Show enhanced antigen-presenting

capacity due to restored lipid metabolism

• More efficiently activate effector T

cells

• Fail to induce immunosuppressive

T-regulatory cells

NO SUCCESS YET NO SUCCESS YET

<10-15% response rate

Can we devise new ovarian cancer immunotherapies based

• n targeting IRE1a/XBP1 in DCs?

Proof-of-concept #1: Nanoparticles that silence IRE1/XBP1 in tumor- resident DCs

siRNA-PEI

siRNA-PEI DAPI

B

XBP1s

siLuc-PEI siXBP1-PEI siIRE1-PEI 0.00 0.01 0.02 0.03

mRNA reative to Gapdh

* *

Nanoparticles encapsulating siRNA are preferentially engulfed by DCs present at tumor sites and reduce IRE1 and XBP1 expression

Therapeutic silencing of IRE1/XBP1 in tumor DCs by nanoparticles enhances anti-tumor immune responses by evoking T cell immunity

TILs Splenic T cells

Cubillos-Ruiz et al. Cell, 2015

Proof-of-concept #2: Therapeutic Dendritic Cell transfer

p53/K-ras + XBP1WT DC p53/K-ras + XBP1KO DC

C D

*

30 45 60 75 2000 4000 6000 8000 10000

days post ADV-Cre Tumor volume (mm3) p53/K-ras + XBP1WT DC p53/K-ras + XBP1KO DC

* *

D

*

d0

d28 d35 d42 Tumor initiation (ADV-Cre) IP transfer of WT

• r XBP1 KO BMDCs

Tumor growth?

Cubillos-Ruiz et al. Cell (2015)

Adoptively-transferred DCs lacking XBP1 induce anti-cancer effects and slow the growth of ovarian tumors

Dendritic cell adoptive transfer instead

• f T cell adoptive transfer in patients?

IRE1α-XBP1 signaling in T cells promotes metabolic dysfunction

• Ovarian cancer triggers activation of IRE1α-XBP1 in T cells to

control their mitochondrial function and anti-tumor activity

• IRE1α-XBP1 signaling promotes T cell metabolic dysfunction

by limiting glutamine influx

• Silencing IRE1α-XBP1 signaling restores T cell metabolic

fitness and anti-tumor capacity in cancer.

Song, Nature, 2018 (in press)

Myeloid-derived suppressor cell (MDSC) function T cell effector capacity Regulatory T cells (T-regs) Immunosuppressive cytokines Dendritic cell (DC) dysfunction

The ER Stress Response Plays a Critical Role in Immunosuppression in the Tumor Microenvironment

Cubillos-Ruiz, Cell, 2015 Song, Nature, 2018 (in press) Condamine, Sci Trans Immun 2017

Tumor cell-intrinsic IRE1a/XBP1 signaling regulates tumor initiating cell function and metastatic capacity

Chen Nature, 2014

Targeting the endoplasmic reticulum stress (ER stress) response comprehensively reprograms the TME

Song et al Nature (in press)

Novel small-molecule IRE1a inhibitors should induce two parallel and mutually reinforcing anti-tumor mechanisms:

Direct inhibition of tumor growth Activation of anti-tumor immunity

Acknowledgments

Weill Cornell Medicine Dana-Farber Cancer Institute Harvard School of Public Health

Cubillos-Ruiz Lab Glimcher Lab Minkyung Song Mahesh Raundhal Han Dong Sarah Bettigole Ann-Hwee Lee Xi Chen Ann-Hwee Lee Sahil Chopra Pedro Silbermann Shang Zhang Thomas Caputo, MD Kevin Holcomb, MD Divya Gupta, MD Lora Ellenson, MD Sandra Shin

The Wistar Institute Jose Conejo-Garcia, MD, PhD Melanie Rutskowski Alfredo Perales-Puchalt Tongji University Qianzi Tang University of North Carolina Qing Zhang Whitehead Institute, MIT Wai Leong Tam Dana-Farber Cancer Institute

Dimitrios Iliopoulos (UCLA) Shirley Liu Myles Brown Maria Hatziapostolou Elgene Lim Min Ni Yiwen Chen

The Wistar Institute Jose Conejo-Garcia, MD, PhD Melanie Rutskowski Alfredo Perales-Puchalt

Supported by the National Institutes of Health and the Cancer Research Institute