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
Cancer Immunotherapy : The End of the Beginning National Academy of Medicine October 15th, 2018 Laurie H. Glimcher, M.D. Dana Farber Cancer Institute Harvard Medical School
Conflicts of Interest Setting the Stage This is the most exciting time in history • Board of Directors, GlaxoSmithKline Co. and for cancer research and care Waters Corporation The need is pressing: • Founder, Quentis Therapeutics • High incidence with 1.7M new cases annually in US • Board of Directors Bristol-Myers Squibb 1997- • Cancer is the leading cause of death for ages 45 – 64 2016 • 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 3 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 Cancer Types by Incidence and Survival 1 5-Year Survival 1 Size of Bubble: % of Cancer Deaths 4 Incidence per 100,000
This is the most exciting time in history for cancer research Setting the Stage Key innovations in cancer treatment and care The need is pressing: • Cancer Genomics: Next generation targeted therapies High incidence with 1.7M new cases annually in US • Cancer is the leading cause of death for ages 45 – 64 • Immuno-Oncology: Activating the immune system • Second-highest cause for 65+ (after cardiovascular) • • Epigenetics: Reprogramming cancer cells to normal behavior Two out of five Americans will develop cancer • • Prevention & Early Detection: Understanding cancer genesis 6 5 Source: CDC 10 Leading Causes of Death by Age Group, United States - 2015
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
Targeted therapy benefits patients with Cancer Incidence Today genomic mutations and has little toxicity Cancer Incidence Today Some cancers have excellent outcomes, but there is still enormous progress to be made Cancer Types by Incidence and Survival With mutation Without mutation 1 5-Year Survival 1 Survival of lung cancer patients treated with osimertinib Size of Bubble: (Drug developed thanks to research by Dana-Farber % of Cancer Deaths scientists) 7 Incidence per 100,000
Targeted Therapy successful for many patients Targeted Therapy successful for many patients September 2011 April 2017 • ALK inhibitor, crizotinib (DF/HCC trial 09-303) • Patient has been cancer-free for 7 years 8 Source: DFCI, Office of the Chief Clinical Research Officer
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? 12
Cancer Immunotherapy “Harnessing the power of the immune system to eliminate tumors” Cancer cell T cells www.livescience.com
T cell infiltration into tumors correlates with prognosis CD3 + TILs NEJM Jan 16, 2003 348; 203-13
A Little History: Coley’s Toxins Dr. William Coley 1893
Effective Immunotherapies Cancer immunotherapies fall into four main buckets Checkpoint Adoptive T Cell Cancer Tumor micro- Blockade Therapy Vaccines Environment 13
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
More Checkpoint Blockade Checkpoint Blockade Inhiibtory antibodies against PD1/PDL1 Dr. Gordon Freeman Dana- Farber Cancer Institute Dr. Tasuku Honjo Dr. Lieping Chen Kyoto University Yale University 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
The Big “But….” Breakthrough immunotherapies still only help a minority of patients and a minority of tumor types Example: Melanoma Tumor Response Rate Treatments Yervoy (CTLA-4) 11% 89% CTLA-4 24% 76% PD-1 Keytruda (PD1) 40% 60% PD-1 + CTLA-4 Opdivo + Yervoy (PD1 + CTLA-4) 0% 20% 40% 60% 80% 100% Response Non-Response Immune Responsive Tumors Today: Melanoma, Lung, Kidney, Bladder, Hodgkin’s Disease, Head & Neck, Liver, GES, MSI Hi colon
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 24
A vaccine for melanoma developed and first in human clinical trial done at DFCI Cathy Wu MD PhD
Effective Immunotherapies Cancer immunotherapies fall into four main buckets Checkpoint Adoptive T Cell Cancer Tumor micro- Blockade Therapy Vaccines Environment 19
Current immunotherapies fail partly due to a highly immunosuppressive tumor microenvironment (TME) Myeloid-derived Regulatory T cells suppressor cell (T-regs) (MDSC) accumulation Immunosuppressive Prostaglandins cytokines T cell exhaustion T cell exclusion Inhibitory Dendritic cell (DC) checkpoints dysfunction
Targeting the endoplasmic reticulum stress (ER stress) response can comprehensively reprogram a hostile tumor microenvironment
The Unfolded Protein (UPR) or Endoplasmic Reticulum (ER) Stress Response • 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)
There are multiple sources of ER stress in the tumor and in the tumor microenvironment (TME) Chemo/radiotherapy Hostile environment Genetic alterations Hypoxia Nutrient deprivation High metabolic demand pH stress ER stress ROS
The Unfolded Protein Response (UPR) is triggered to correct this local ER stress Chemo/radiotherapy Hostile environment Genetic alterations Hypoxia Nutrient deprivation High metabolic demand pH stress ROS ER stress UPR IRE1 a ATF6 PERK Protein Protein Translation Apoptosis Secretion folding degradation
The IRE-1/XBP-1 Signaling Pathway Accumulation of misfolded proteins IRE-1 Hypoxia,nutrient deprivation ER lumen Kinase domain Cytosol Endoribonuclease domain IRE1 endonuclease cleaves its substrate: Converts XBP1 unspliced to XBP1 spliced XBP1s Nucleus Quality control Chaperones ER expansion Foldases Autophagy ERAD Schroder et al., Annual Review Biochem 2005 Hetz et al., Molecular Cell 2009 Rojas-Rivera D. Adv Exp Med Biol 687; 33-47. 2010
ER Stress in Cancer IRE1/XBP1 in ovarian cancer: targeting the immune system tumor microenvironment
IRE1a/XBP1 signaling directly promotes dendritic cell dysfunction Juan Cubillos-Ruiz Cell, 2015
Ovarian Cancer (OvCa) Most lethal gynecologic cancer and the 5 th most frequent cause of cancer deaths in women 1 in 95 women will die of ovarian cancer
Current treatments show poor success (surgery and chemotherapy but PARP inhibitors now available) Ovarian cancer 5-year survival rates 100 80 Survival rate (%) 60 40 20 1975-77 1987-89 2002-2008 Overall survival rate: ~40% High recurrence rate due to multidrug resistance
Dysfunctional Dendritic Cells are Key Mediators of Immune Suppression in the Ovarian Cancer Microenvironment • Release pro-angiogenic factors Dendritic cell (DC) • Promote tumor growth • Express immunosuppressive molecules • Unable to present antigens to T cells T cell • Don’t support T cell function Immunosuppressive DCs are the Conejo-Garcia and Coukos. Nature Med . 2004 Huarte, Cubillos-Ruiz and Conejo-Garcia. Cancer Res . 2008 “brakes” in ovarian cancer Cubillos-Ruiz and Conejo-Garcia. J. Clin. Invest. 2009 Cubillos-Ruiz and Conejo-Garcia. Cancer Res . 2012 Does ER Stress in dendritic cells contribute to a Scarlett, Cubillos-Ruiz and Conejo-Garcia. J Exp Med . 2012 hostile tumor microenvironment? Cubillos-Ruiz and Glimcher. Cell . 2015
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