Disclosure Information. Mary L. Disis

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1 Disclosure Information Mary L. Disis I have the following financial relationships to disclose: Consultant for: VentiRx, Celgene, Emergent, EMD Serono Speaker s Bureau for: N/A Grant/Research support from: VentiRx, Seattle Genetics Stockholder in: VentiRx, EpiThany Honoraria from: N/A Employee of: University of Washington (inventor named on patents) Emerging Immunotherapies for Breast Cancer Mary L. (Nora) Disis University of Washington Fred Hutchinson Cancer Research Center Seattle, WA ndisis@uw.edu 1

2 Clinically effective anti-tumor immunity Bindea et al, Curr Opin Immunol, 2010 High magnitude Type I CD4 (Tbet+), CD8 (GZB+) Memory Low levels of regulatory cells Fridman et al, Nat Rev Ca, 2012 Dissecting the steps of an anti-tumor immune response Antigen present on/in tumor Antigen presentation by APC T-cells traffic to tumor Smyth et al, Nat Immunol,

3 Antigens present on/in tumors: Aberrantly expressed self Virus Like Mutated Self Non-mutated MUC-1 HER2 Cyclin B1 NY-ESO IL-12, IL-2, IFN-g, TNF-a IL-4, IL-5, IL-10, TGF-b DeNardo et al, Ca Met Rev, 2010 Antigens present on/in tumors: Neo-antigens TNBC Melanoma patients treated with ipilimumab Alexandrov et al Nature, 2013 Snyder et al, NEJM, 2014 Total mutation rate in breast cancer: 1.66/Mb (range: ) Banerji et al, Nature,

4 Tumor lymphocyte and CD8 + T- cell infiltrates in breast cancer % Individuals n=3380 n=5536 Stanton et al, 2015 LPD: pathologic CR in neoadjuvant, DFS, OS Approaches to optimizing a therapeutic immune response Butt et al Oncogene, 2013 Increase effector T-cells Trastuzumab Vaccines Adoptive T-cell Therapy Enhance existing immunity Checkpoint inhibitors Cytokine Therapy (IL-15, IL-7) Depletion Tregs, MDSC MoAB (X-IL-10, TGFb) Modulate the tumor microenvironment to support evolving immunity 4

5 Progress for the application of immune therapy to breast cancer TN+ Most likely to have CD8 HER2+ TIL, responds to immune therapy HR+ Least likely to have TIL Trastuzumab acts as a vaccine in some patients No immunity No immunity + Immunity + Immunity n=97 ***p<0.001 Baseline cspw/10 6 PBMC *** *** Low Intermediate High Stanton et al,

6 Is the primary mechanism of action of trastuzumab to stimulate adaptive immunity? % RFS Alliance N9831 n=3,505 HER2 positive breast cancer: evaluation of stromal TIL Lymphocyte y Predominant Non-Lymphocyte y Predominant Chemo Chemo+ Trastuzumab Log rank=0.21 Chemo+ Trastuzumab Log rank=< Chemo Years from Randomization Perez et al, SABC, 2014 Trastuzumab does not matter! Will length of trastuzumab treatment be dictated by measurement of therapy induced immunity? Levels of tumor educated T-cells NONE 1. Immunologically inert (host factors) 2. Generation of tumor specific T-cells INTERMEDIATE LOW ACTIVATION 1. Generation of tumor specific T-cells 2. Up regulation of immune activation molecules Type I immunity enhances the effects of chemotherapy Anti-proliferative Anti-angiogenic Cytotoxic Ferris et al, JCO, 2010 HIGH HIGH ACTIVATION (ICOS, CD69?) ALREADY AT A MAXIMAL RESPONSE 1. EXHAUSTION 2. DELETION 3. ANERGY ns 10% for C+T 6

7 MMTV-huHER2-Tg mice Large tumors 43% response rate HER2 transfected implanted tumors icd3-tg mice Inc. PDL-1 on tumor cells Combination superior Tumor immune microenvironment? What happens when you activate highly activated T-cells? Unleash existing immunity Activate Stimulatory signals **** Suppress Inhibitory signals Topalian et al, JCO, Use early in treatment course in a subset of breast cancer: mutation status, high levels of TIL? 7

8 ORR to pembrolizumab (anti-pd-1) across multiple tumor types Monotherapy, advanced stage TNBC ESMO, 2014 Alexandrov et al Nature, 2013 Patterns of response identical to melanoma and NSCLC Change from baseline % response 4% CR -80 On treatment Discontinued treatment n=32 Time, weeks 60% 2 previous tx 28% response >60% durable 1 year Topalian et al, NEJM, % response Grade 3-5 toxicities, 16% Brahmer et al, NEJM,

9 Mining phenotypes for mechanisms of tumor induced immune escape 60 Post-NAC (RFS) 100 Low (0-10%) Int (11-20%) 80 Hi (21-70%) Trend: p= Time (months) Balko et al, SABC, 2014 RAS-RAF-MEK-ERK pathway activation: Activation reduces Type I cytokine production, increases transcription of IL-1, upregulates PD-1 and PDL-1 and down regulates MHC I BRAF inhibitors increase both CD4 and CD8 TIL: Restores production of TNF-a and IL-12 in local DC and enhances production of IFN-g by CD4+ T-cells Immunotherapeutic approaches to breast cancer Tumor immune environment Level of TIL Phenotype of TIL (Type I, II and regulatory) Provide Type I immunity Elicit Type I immunity Release Type I immunity Disis et al, CCR Focus, 2013 Propagate immune response 9