Exploring TIM-3 biology: from bench to biomarkers

Transcription

1 NIBR EIO/ Oncology Translational Research Exploring TIM-3 biology: from bench to biomarkers Jennifer Mataraza Translational Immuno-Oncology Novartis Institutes for BioMedical Research World CDx, Boston, October 18, 2017

2 Translational Research Program Critical for identifying novel IO combination approaches To understand the immune microenvironment before and following perturbations To understand how cancers adapt and/or develop resistance to therapies To understand why our treatments fail (wrong target, failed pharmacology, unanticipated adaptation) Critical for developing novel combinations that are clinically relevant 2

3 The TIM-3 pathway in cancer Anderson, Cancer Immunol Res by American 3 Association for Cancer Research

4 Accumulation of inhibitory receptors on dysfunctional T cells ID s multiple targets Accumulation of inhibitory receptors is associated with increasing T cell dysfunction during chronic antigenic stimulation Wherry lab (U Penn) Mellman et al (2011) Nature 480:480 4

5 T cell exhaustion develops without PD-1 PD-1/TIM-3 and PD-1/LAG-3 expression correlation Odorizzi et al (2015) J Exp Med Further upregulation of multiple checkpoints and exhaustion signature seen in PD-1 -/- T cells Correlation of PD-1/LAG-3 and PD- 1/TIM-3 seen in multiple cancer indications 5

6 TIM-3: Areas of Exploration Biomarkers Agonist or antagonist? TIM-3 Unknowns Dosing Regimes Key cells to target 6

7 TIM-3 and PD-1 blockade synergize in preclinical mouse models TIM-3/PD-L1 CT26 TIM-3/PD-1 CT26 α-tim-3 α-pd-1 α-tim-3/ α-pd-l1 α-tim-3/ α-pd-1 Sakuishi et al (2010) JEM Ngiow et al (2011) Cancer Res 7

8 Preclinical cancer models demonstrate the role of TIM-3 on multiple TIL subsets CD4 and CD8 depletion or IFN-γ KO reduces anti-tim3 impact MC38 Depletion of Foxp3+ T cells enhances TIM-3 blockade anti-tumor activity CT26 FOXp3 depletion FOXp3 depletion +anti-tim3 Ngiow et al (2011) Cancer Res Sakuishi et al (2013) OncoImm 8

9 TIM-3 is highly expressed on TILs TIM-3 highly enriched on tumor infiltrating Tregs in syngeneic tumor models Tumor Infiltrating CD8+ effectors express high levels of TIM-3 TIM-3 expressed highly on human tumor associated DC Sakuishi et al Oncoimmunology. (2013) Ngiow et al Cancer Res (2011) Chiba et al Nature Immunology (2012) 9 Healthy donor Patient

10 TIM-3 correlation in the TCGA database with a myeloid signature T cell markers Myeloid markers TIM-3 POS TIM TIM-3 TIM-3 NEG Monocytes PD-1 TIM-3 correlates with tumor myeloid signature Most abundant TIM-3 on normal PBMCs is on myeloid cells 10

11 What is the function of TIM-3 on myeloid and T cells? TIM-3 TIM-3L TIM-3L TIM-3 APC T? APC T Ab MoA? Antagonist Agonist Multiple possible mechanisms: on T cells on myeloid cells Indirect impact on T cell and/or myeloid cells Can we ask these questions by manipulating TIM-3 in either cell subset? 11

12 TIM-3 in myeloid cells Evidence for inhibitory role - Blockade enhances IL-12 secretion in myeloid cells (Zhang et al 2011 PLoS One, Zhang et al 2012 J Leukoc Biol) 12

13 TIM-3 and PD-1 expression on RCC TILs Dominant TIM-3 SP myeloid cells; PD-1+TIM-3+ DP CD8+ in TILs TIM-3+PD-1+ TIL 40.5 PBMC Dominant TIM-3+ CD14+ cells and PD-1+ CD8+ T cells CD Tumor PBMC CD14+ CD8+ CD14+ CD8+ CD14+ TIM TIM-3+ Tumor PBMC CD14+ CD8+ CD14+ CD8+ PD-1 13

14 Using TIM-3 KO mice to explore biology Unknown DC/MΦ MDSC Treg CTL 1) Is there a difference in tumor growth? 2) Are there any changes in TIL populations? 3) Are there functional differences in TIL? Woo et al (2012) Can Res 14

15 Loss of TIM-3 enhances proinflammatory cytokines in murine splenocytes with ex vivo stimulation SEB, 1ng/mL, day 3 SN harvest; n=3 mice per group Data representative of two independent experiments No difference in T cell, myeloid cell frequencies within the spleen (data not shown) 15

16 TIM-3 is expressed most highly on DC subsets TIM-3 is most highly expressed on cdc CD45 Ly6C MHC-II CD11b Ly6G F480 cdc: CD45 + CD11b + Ly6C low MHC-II + Ly6G - F480 - Mac:CD45 + CD11b + Ly6C low MHC-II + Ly6G - F

17 TIM-3 expression is increased in the setting of anti-pd-1 resistance TIM3 expression higher in cells from resistant effusions=re (no PD-1 therapy =CE, surgically resected primary tumors=pt) TIM-3 + T-cell population in resistant patients majority of TIM-3 + T cells bound the therapeutic antibody-higg + (Same for TIM3 + T reg ) Koyama et al (2016) Nat Comm 17

18 MBG453: a first-in-class, high affinity, PtdSer-blocking mab Characteristics Isotype Affinity human TIM-3 (Biacore, K D ) Affinity human TIM-3 (cells, K D ) Affinity cyno TIM-3 (cells, K D ) Blocking PtdSer (IC 50 ) MBG453 higg4 (S228P) 0.167±0.008 nm 0.5±0.1 nm 0.9±0.1 nm 6.4 nm MBG453 TIM-3 IgV MBG inhibits PtdSer, but not Gal-9, binding site on TIM-3 FG loop PtdSer Ca 2+ CC loop G F Asn33 Asn99 Galectin-9 binding sites Heavy Light 18

19 TIM-3 blockade enhances IL-12 and TNF-α secretion by DCs - Peripheral monocytes differentiated to immature DCs - Stimulated 1 µg/ml LPS/R848 for 72 h - Data representative of four independent donors *p < 0.05; ****p < TIM-3 blockade directly on DCs enhances IL-12 and TNF-α secretion 19

20 In ex-vivo assays, MBG453 impacts both T cell and myeloid cytokines PD-1/TIM-3 co-blockade enhances TNFα/IFN-γ DP+ CD4+ T cells (SEB stimulation) PD-1/TIM-3 co-blockade enhances IL-12 secretion from patient PBMCs (SEB stimulation) PDR001 +MBG453 MBG453 PDR001 higg4 20

21 PD-1 and TIM-3 co-blockade increases cytokine responses in allo MLR MLR: allo DC/T cell response Donor 1 i-modcs Donor 2 CD4+ T cells + Ab (25 µg/ml) (PDR001: anti-pd1) Cytokine d3, d6 TIM-3 blockade synergizes with PD-1 blockade to augment Th1- and myeloid-derived cytokines 21

22 Model: TIM-3 blockade on myeloid cells impacts CD8 T cell IFN-γ secretion Freeman et al (2010) Imm Rev Apoptotic clearance: anti-inflammatory effects? MBG453 and PDR001 blockade synergize to increase inflammatory cytokine secretion in multiple in vitro assays (as in preclinical models with surrogate mabs) MoA for TIM-3: On T cells, DCs or both? 22

23 MBG453X2101- FIH study in solid tumors Clinical trials.gov identifier: NCT Dose escalation MBG453 Advanced solid tumors MTD/ RDE Indication(s) based on antitumor activity observed in dose escalation Dose escalation MBG453 + PDR001 Advanced solid tumors MTD/ RDE Melanoma (PD-1/PD-L1 naive and pretreated) NSCLC (PD-1/PD-L1 naive and pretreated) RCC (PD-1/PD-L1 naive and pretreated) Biomarker challenges: TIM3 biology potentially affects multiple immune cell types = potentially difficult to understand PD or single agent effects? 23

24 What can we learn about MBG453 effect in the TME? Core needle biopsies in FFPE pre and post treatment IHC for CD8, PD-L1, TIM-3 and CD163 RNAseq analysis Questions: Does pre-existing or increase in CD8 T cell infiltrate predict response? Does treatment cause an increase in CD8 T cell infiltration? Does TIM-3 expression on TILs predict responsiveness or change on treatment? In patients with pre-existing M2 macrophages, does treatment result in increased CD8 infiltration? Can we identify gene signatures that predict response or identify PD/biomarkers? TN TN TIM-3 IHC staining in melanoma S=Stroma TN=Tumor nests Red arrows=tim3 + lymphocytes S S 24

25 Monitoring for peripheral blood changes following MBG453 treatment Plasma and PBMC collections Pre-treatment and multiple timepoints post-treatment Questions: Are there cytokine signatures at screening that predict response? Can we identify cytokines that change with time, or dose? Can we identify cytokine alterations on treatment that correlate with response? Can we identify changes in peripheral blood populations that correlate with response? TIM-3 expression on normal PBMCs A. TIM3 expression on NK, CD4 and CD8 T cells B. TIM-3 expression on myeloid cells 25

26 Beyond anti-pd-1 combinations Depletion of DC reduces responses to anti-tim-3 treatment in syngeneic models 26

27 Potential anti-tim3 combination partners Vaccines/Immune Priming IL-15 STING TIM-3 T cell modulation PD-1 PD-L1 TGF-β LAG-3 TIM-3 GITR CAR-T Tumor microenvironment PD-1 LAG-3 IL-15 PD-L1 TGF-β CSF-1 A 2A Adenosine Receptor TIM-3 GITR Image adapted from Mellman I, et al. Nature. 2011;480:

28 Acknowledgements NIBR Exploratory Immuno-oncology Catherine Sabatos-Peyton Pushpa Jayaraman Pranal Dakle Elizabeth Choi Nidhi Patel Radha Ramesh Lisa Baker Fiona Sharp Amy Allaire Xiaomo Jiang Sumana Ullas Tyler Longmire Jennifer Johnson Eva d Hennezel Anna Magracheva Reshma Singh Ben Primack Tingyu Liu NIBR Onc Bioinformatics Hans Bitter Kenzie MacIsaac Lellean JeBailey 28 NIBR Onc/Imm-onc Management Glenn Dranoff Jeff Engelman Peter Hammerman NIBR CPC Tiancen Hu Xiaoping Zhu Rajiv Chopra Kirk Clark Travis Stams NIBR OTR/TCO Margaret McLaughlin Jian Xu Luigi Manenti Lilli Petruzzelli Lew Petryk Jens Lohrmann Panos Nikolopoulos Sabine Gutzwiller Kitty Wan Amy Lambert Seema Tomer Jonny Wood Susan Trinker Andrew Stein Maura Metzler

29 Thank you