Lymphoma and CLL EHA Madrid Professor John G Gribben Centre for Haemato-Oncology Barts Cancer Institute, London, UK

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1 Lymphoma and CLL EHA Madrid 2017 Professor John G Gribben Centre for Haemato-Oncology Barts Cancer Institute, London, UK

2 Conflicts of Interest J Gribben I have the following financial relationships to disclose. Honoraria: Abbvie, Acerta, AZ/Medimmune, Celgene, Gilead, Janssen, Kite, Morphosys, Pharmacyclics, Roche/Genentech, TG Therapeutics Grant Funding: Clinical Trials: NIH, Cancer Research UK, MRC, Wellcome Trust, Janssen, Acerta PI for trials sponsored by Roche/Genentech, Pharmacyclics, Janssen, Gilead, Takeda, Merck, Epizyme TG Therapeutics, 2

3 Objectives To overview and highlight what is new and of interest in lymphoma and CLL at EHA Direct to sessions of interest Provide background

4 Big Picture Lymphoma CLL Immunotherapy coming to the fore Updates on novel antibodies Are novel agents replacing chemotherapy Novel agent combinations why should we do this?

5 Timetable Thursday corporate symposia

6 Friday Educational sessions Indolent lymphoma Hall A Immunotherapy Hall A Simultaneous sessions Aggressive NHL Hall B Lymphoma biology Room N10 Presidential symposium Hall A HD18 Trial of German Hodgkin Study Group Updates in Hematology CAR-T cells

7 Saturday morning Educational sessions Immunotherapy Hall A Indolent lymphoma Hall A CLL Hall B Scientific working group Diagnosis and follow up of lymphoma Hall C Genomics and epigenomics in CLL Room N105 Mantle cell lymphoma Room N103 Simultaneous sessions Hodgkin and indolent lymphoma Hall B

8 Saturday afternoon Hematology in Focus Richter transformation Hall B Rare lymphoma subtypes Hall C EHA-ESH Joint symposium Doctor Patient communication Room N109 Simultaneous sessions Improving prognostication in CLL Hall B Relapsed/refractory aggressive NHL Hall C

9 Sunday Simultaneous sessions Targeted therapy in CLL Hall A Follicular lymphoma Hall B Educational session CLL Hall A Aggressive lymphoma Hall B Aggressive lymphoma Hall B Late breaking abstract CAR T cells in lymphoma will be presented Plenary session

10 Making Sense of all of This Your Lymphoma PhD in 10 minutes! What are CAR T cells? What are Checkpoint inhibitors? Do PET scans matter in follicular lymphoma? Is chemotherapy over in CLL?

11 Outline adaptive immunity and the role in T cells in anti-tumor responses, T cells dysfunction in cancer and how to reverse this, rationale for CARs, different CAR constructs and the importance of the signaling and co-stimulatory domains, CAR-T studies going forward (other tumor types, combination with checkpoint inhibitor)

12 Why Does Our Immune System Fail to Eradicate Cancer T cells fail to eradicate cancer because cancers have developed mechanisms that drive changes in the host immune response to generate unique microenvironments that are conducive to cancer cell growth rather than attack the cancer cells. by understanding the molecular processes that drive these changes, we can develop therapeutic strategies to target the microenvironment to improve the results of treatment and/or We can augment T cell responses to overcome these defects

13 Loss of Naïve and Expansion of Effector Memory T Cells in PB Age Matched 19% 43% 16 % 4 %n 49 % 27% 31 % Healthy 11% CLL Naive T CM T EM T EMRA Riches JC, et al. Blood. 2013;121:

14 High expression of inhibitory ligands on Tumor cells and inhibitory receptors CD272 (BTLA) and CD279 (PD-1) on T cells In situ expression analysis using a CLL and FL TMA Significantly increased expression of CD200 and CD274 (PD-L1) on FL cells and CD279 (PD-1) on CD3 + T cells was found in poor prognosis patients Ramsay et al Blood. 2012;120:

15 Impaired T-Cell Motility in TILs Healthy T-cells TILs IMiD treated TILs Kiaii et al JCO 2013, Ramsay et al Blood 2013.

16 Pseudo-exhaustion of T cells in CLL CD244; CD160, PD1: CTLA4, TIM3,LAG3:* CLL CD8+ T proliferation: CLL CD8+ cytotoxicity : Granzyme packaging: Interferon-γ, TNFα:* T cell IL2:* CLL Zenz Blood 2103 Riches et al Blood. 2013;121:

17 Inhibitory axes are important mediators of CLL induced global T-cell defects inhibitory ligands (Ramsay et al. Blood 2012) CD200 (OX2) CD270 (HVEM) CD274 (PD-L1) CD276 (B7-H3) CLL cell T cell chronic activation (Riches et al. Blood 2013, Brusa et al. Haematologica 2013) CD160 CD279 (PD-1) 4 E 8 8 dysregulated genes synapse formation N E M M subsets effector function exhaustion

18 Immune Checkpoint inhibitors Blocking immune checkpoints may promote endogenous antitumor activity PD1: Inhibitory receptor on activated T-cells, B- cells, NK and myeloid cells. Inhibition of T-cell activation when engaged by ligands (PDL1/2) PD1 expressed on T- cells when exposed to tumor, and associated with exhaustion. Blocking can restore function Greaves and Gribben Blood 2013.

19 Ways to Improve Immune Responses against Lymphoma Agents of interest include but are not limited to Lenalidomide and other ImIDs Anti-PD1/PDL-1 mabs Anti-CD47 mabs Anti-CD137 mabs CSF1-R antagonists CAR T cells Signal transduction inhibitors impact not only malignant B cells but also the microenvironment

20 The Power of the Chimeric Antigen Receptor (CAR)! or CD28

21 Designing a Chimeric Antigen Receptor 5 LTR y scfv Hinge Costim z 3 LTR Antibody SIGNAL 2 Costimulatory molecule TCR zeta chain SIGNAL 1

22 Redirecting the Specificity of T Cells Different transduction systems to get CARs into T cells Retroviral transduction Lentiviral transduction versus Nonviral transduction (Sleeping Beauty) Native TCR T cell CTL019 cell Anti-CD19 CAR construct CD19 Dead tumor cell Tumor cell

23 Clinical Trials Using CAR-T Lymphocytes Major limitation to overcome is a lack of persistence of CAR-transduced T cells in vivo Open CAR-CD19 studies are attempting to improve T-cell persistence using different strategies

24 Improving Persistence Improving costimulation Activation of homeostatic expansion mechanisms Modifying the T cells to transduce Combine with virus-specific cytotoxic T cells (Baylor/Cruz et al. Blood. 2013) CD3/28 stimulated T cells (multiple centers) Fixed ratio of CD4 and CD8 CM T cells (Seattle/ Turtle et al. J Clin Invest. In press)

25 Increasing Potency Across Generations: Not All CARs Created Equal? Classic CARs Sports CARs Muscle CARs Sadelain et al

26 CD19 CARs: Original CAR and CARs in Clinical Trials Juno Kite Bluebird bio Novartis Juno

27 Remission after Infusion of CAR T cells Before Treatment 6 Months After Treatment <50% patients receiving anti-cd19 CAR T cells after lowdose chemo required ICU admission. Overall response rate: 73%, CR in 55%, PR in 18%

28 The Cytokine Release Syndrome* Definition, Treatment, Prevention Expansion of the CAR T cells in patients leads to release of cytokines inclduing IL6 Associated with high spiking fevers Neurotoxity often requiring ITU admission Davila et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine. 2014;6:224ra225. Maude et al. Managing cytokine release syndrome associated with novel T cellengaging therapies. Cancer Journal. 2014;20: Lee et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124: Brudno and Kochenderfer. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood pii: blood

29 CD19 CARs: Issues for Broadening Applicability? Management cytokine storm/macrophage activation syndrome Potential for immune escape and antigen loss when only targeting single antigen Complex study for multicenter translation Management of prolonged B-cell depletion Expensive? Insurance issues? Still unclear which CAR attributes are important for potency..

30 What Is the Ultimate Potential for CD19 CAR T-Cell Therapy? With long-term T-cell persistence and controlling toxicities can we replace SCT for patients? Or improve outcome with a combination approach (SCT, checkpoint blockade, vaccines, etc.)?

31 Cell Therapy for Cancer: The Vision Lymphoma Acute Leukemia Neuroblastoma Brain Tumors Sarcomas Surgery Chemotherapy Small Molecules Checkpoint Inhibitors Antibodies Disease Burden DC Vaccines T Cells/CARs NK Cells Tumor Seeking MSC Minimal Residual Disease Sources: Autologous/Allogeneic Cure

32 Repairing T-cells T cell CLL

33 Repairing T-cells T cell

34 What About CLL? It is all about targeted therapies Progression-Free Survival Overall Survival Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) NR 57% O Brien et al. ASH 2016; abstract 233 (oral presentation)

35 Patients remain on these drugs a long time Cumulative frequency of grade 3 adverse events over 5-year follow-up Non-hematologic 5% Hematologic Infectious R/R TN R/R TN R/R TN Grade 3 Grade 4 Grade 5 O Brien et al. ASH 2016; abstract 233 (oral presentation)

36 Overall survival (%) Progression-free survival (%) Ibrutinib effective even in our worst patients PFS Median time on study: 28 months Estimated 12-mo PFS, % (95% CI) Estimated 24-mo PFS, % (95% CI) Estimated 30-mo PFS, % (95% CI) 80% (74, 84) 63% (57, 69) 55% (48, 62) Months from initiation of study OS Estimated 12-mo OS, % (95% CI) Estimated 24-mo OS, % (95% CI) Estimated 30-mo OS, % (95% CI) 85% (80, 89) 75% (68, 80) 67% (59, 74) Months from initiation of study Jones J, et al. EHA 2016: abstract S429 (oral presentation)

37 Venetoclax also effective in our worst patients Duration of Response (N=85) PFS and OS (N=107) 12-month estimates: All responders: 84.7% CR/CRi/nPR: 100% MRD-negative: 94.4% 12-month estimates (95% CI): PFS: 72.0% (61.8, 79.8) OS: 86.7% (78.6, 91.9) Stilgenbauer et al. ASH 2015; abstract LBA-6 (oral presentation)

38 Can we optimize treatment - combine drugs and stop therapy Relapsed/progressing CLL (or treatment niave) BCR inhibitor plus venetoclax Response No Response Test BM MRD Neg Alternative- Idelaliisib Transplant STOP Rx

39 Summary Immunotherapy approaches showing success in DLBCL Novel antibodies in CLL and FL Novel agent combinations in CLL Enjoy the meeting Pace yourself!