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
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, 2001 2
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: 0.47-10.5) Banerji et al, Nature, 2012 3
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
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 5000 2000 2000 1600 1200 800 400 0 *** *** Low Intermediate High Stanton et al, 2015 5
Is the primary mechanism of action of trastuzumab to stimulate adaptive immunity? % RFS 100 90 80 70 60 50 40 30 20 10 0 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=<0.0001 Chemo 0 2 4 6 8 10 0 2 4 6 8 10 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
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
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 100 80 60 40 20 0-20 -40-60 19% response 4% CR -80 On treatment Discontinued treatment -100 0 8 16 24 32 40 48 56 n=32 Time, weeks 60% 2 previous tx 28% response >60% durable 1 year Topalian et al, NEJM, 2012 10% response Grade 3-5 toxicities, 16% Brahmer et al, NEJM, 2012 8
Mining phenotypes for mechanisms of tumor induced immune escape 60 Post-NAC (RFS) 100 Low (0-10%) Int (11-20%) 80 Hi (21-70%) 40 20 Trend: p=0.0005 0 0 50 100 150 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