Charles George Drake, M.D., Ph.D.

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2 Charles George Drake, M.D., Ph.D. Eleventh European International Kidney Cancer Symposium April 2016 Crowne Plaza Barcelona Fira Center, Barcelona, Spain

3 Immune Checkpoint Inhibitors in RCC: How Can we Get More (Most) Patients to Benefit? Charles G. Drake MD / PhD Co-Director Cancer Immunology Program Professor: Oncology, Immunology and Urology The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center And The Brady Urologic Institute

4 Disclosure Consultant / Advisor: Agenus, Compugen, Dendreon, NexImmune, Novartis, ImmunExcite, Janssen, Lilly, Merck, Pierre Fabre, Potenza, Roche / Genentech, Tizona Sponsored Research Agreement: Aduro Biotech, Bristol Myers Squibb, Compugen, Janssen Ownership / Patents: AZ Medimmune, Bristol Myers Squibb, Compugen, Potenza I will discuss off label use and/or investigational use in my presentation

5 What We ve Got 22% Overall Response Rate (ORR) Motzer RJ et al. NEJM 2015: 373, 1803

6 Changes in target lesions from basline (%) M Ball, M Gorin, M Johnson, C Drake and M. Allaf (unpublished) What We Want Month since treatment initiation

7 How to Get From Here to There Combinations with VEGF-targeted agents Combined Checkpoint Blockade Stepping On the Gas: Cancer Vaccines Immune Agonists Manipulating the Tumor Microenvironment IDO inhibition CSF-1R inhibition Treg Depletion Identifying Combination Regimens Direct study of TIL Neo-Adjuvant Trials Thinking Outside of the Box: Blocking innate immunity (IL-1, TNF-alpha etc)

8 Anti-PD-L1 (Atezolizumab) + VEGF Blockade (Bevicizumab) VEGF Blockade Increases T cell Trafficking into Tumor Microenvironment 40% Overall Response Rate (ORR) VEGF Promotes Inhibitory Dendritic Cells / MDSC VEGF Blockade has Anti-Tumor Effects Bendell, Jones, Mier, Sznol, McDermott ESMO 2015

9 Anti-PD-1 (Nivolumab) + VEGF Blockade (Sunitinb) 52 % Overall Response Rate (ORR) (S+N) 82 % Grade III / IV AE Amin et. al. ASCO 2014

10 Anti-PD-1 + Anti-CTLA-4 PD-1 Increases CD8 T Cell Function / Trafficking 38 % Overall Response Rate (ORR) 34 % Grade III / IV AE CTLA-4 Highly Expressed on Treg in Tumor Microenvironment Additional Inhibitory Checkpoints LAG-3 TIM-3 TIGIT Hammers HJ et al ASCO 2014

11 Combination First Line Studies Phase III Ipilimumab / Nivolumab vs. Sunitinib Atezolizumab / Bevicizumab vs. Sunitinib Avelumab / Axitinib vs. Sunitinib Pembrolizumab / Axitinib vs. Sunitinib

12 Vaccination To Convert Non-Inflamed RCC into An Immune-Sensitive Target?

13 Vaccines May Require PD-1 / PD-L1 Blockade to Achieve Maximal Benefit (The Problem of Adaptive Immune Resistance) Tumor T Cell IMX-9001: A multi-peptide based vaccine AGS-003: An autologous DC vaccine Interferon g Newlink Renal (HAR) Immunotherapy : A transduced cell line-based vaccine TUMOR PD-L1 T Cell Pardoll and Drake, JEM 2014 Adaptive Up-Regulation Of PD-L1 Turns T Cell OFF

14 Immune Agonists: Stepping on The Gas Activate Dendritic Cells CD40 Pathways to Activate CD8 / Deplete Treg GITR OX40 41BB CD27 deluca and Sommers. Nat. Rev. Immunol. (2012)

15 Targeting the Tumor MicroEnvironment (TME): #1 IDO Inhibition Preliminary results from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with selected advanced cancers Evaluable patients*, n (%) Melanoma (n=7) RCC (n=5) TCC (n=2) NSCLC (n=2) EA (n=2) SCCHN (n=1) ORR (CR+PR) 4 (57) 2 (40) 1 (50) 1 (50) 1 (50) 1 (100) CR 2 (29) PR 2 (29) 2 (40) 1 (50) 1 (50) 1 (50) 1 (100) SD 2 (29) 2 (40) 0 1 (50) 0 0 DCR (CR+PR+SD) 6 (86) 4 (80) 1 (50) 2 (100) 1 (50) 1 (100) PD 1 (14) 0 1 (50) Not assessable 0 1 (20) (50) 0 *Patients with 1 post-baseline response assessment or discontinued from study or died before response could be assessed. Mellors and Munn, Nat. Rev. Immunol. (2004) Gangadhar TC et al, JITC 2015

16 Tumor Targeting the Tumor MicroEnvironment (TME): #2 Targeting Suppressive Myeloid Cells / Macrophages Isotype Tumor Volume (mm 3 ) Castration-Resistant Myc-CAP Model Degarelix + acd115 Degarelix Degarelix + JNJ Anti-CSF-1R CSF-1R TKI Days Post Castration Tumor Anti-CSF-1R Tumor Volume (mm 3 ) Degarelix + acsf1r Degarelix Degarelix + JNJ Pyontek et al, Nat. Med. (2013) Days Post Castration Lopez-Bujanda and Drake, Unpublished

17 Day 0: Tumor Implantation Targeting the Tumor MicroEnvironment (TME): #3 Depleting Regulatory T Cells Day 7, 9: Checkpoint Inhibitor Day 5: LM-MEL Checkpoint Inhibitor Francica, Ghasmedzeha and Drake Unpublished

18 Identifying Combinations

19 Preliminary Data: RNA-Seq on RCC TIL # of Cells Patient 2 Patient 3 Patient 4 Patient 7 Patient 12 Patient 15 Tumor Stage T1b T1b T1a T3a T3a T3a PBMC Naïve CD8+ 65, ,000 92, ,000 80, ,000 PBMC Naïve CD4+ 600, ,000 64,000 1,800,000 67,000 1,000,000 PBMC Treg 92,000 90,000 43, ,000 68, ,000 Tumor Treg 9,000 36,000 10,000 82,000 80,000 43,000 Tumor Antigen Experienced CD8+ 106, ,000 50, , , ,000 %CD8+CD45RO+ of Lymphocytes %Treg of Lymphocytes Ratio CD8/Treg Low Grade Case High Grade Case

20 Tumor Treg vs PBMC CD4 Activated (N = 682) PBMC CD4 Naive PBMC CD4 Activated PBMC CD4 Treg PBMC CD8 Naive PBMC CD8 Activated CD4 Act.CD8 Act. CD4 N. CD8 N.PBMC Treg TIL CD8 TIL Treg Tumor CD8 Antigen Experienced Tumor CD4 Treg

21 CD8 TIL vs PBMC CD8 Activated (N = 149) PBMC CD4 Naive PBMC CD4 Activated PBMC CD4 Treg PBMC CD8 Naive PBMC CD8 Activated CD4 Act. CD8 Act. PBMC Treg TIL Treg TIL CD8 CD4 N. CD8 N. Tumor CD8 Antigen Experienced Tumor CD4 Treg

22 A Neo-Adjuvant Trial To Identify Potential Combination Regimens Allaf, Drake, Johnson, Ball, Hammers and Gorin: Open and Accruing

23 Can Immunotherapy Accelerate Disease Progression? (Phase III Data, Ipilimumab in Metastatic Prostate Cancer) Kwon E., Drake CG. et al. Lancet Oncology (2014)

24 Can Immunotherapy Accelerate Disease Progression? (Phase III Data in RCC, subgroup analysis) Favorable HR: 0.82 p = 0.59** All patients HR: 1.34 p = 0.08* Con: 33.7 mo Vac: n.r. Con: Median OS: n.r. # Vac: Median OS: 33.1 mo Intermediate HR: 1.52 p < 0.05** # n.r. = not reached * logrank statified on risk group ** unstratified logrank Rini B. et al. ESMO (2015) Con: n.r. Vac: 27.8 mo

25 A Murine Model Suggests A Mechanism (and An Approach) Vastly Elevated Innate Cytokines in OLDER Mice Bouchlaka M et al. JEM 2013;210:

26 Conclusions Numerous Pre-Clinical Examples of Synergy Between anti-pd-1 / PD-L1 and X Immuno-Activating Potential of Local Therapy (RT, Cryotherapy, Surgery) Clinical Studies Showing Additive Activity Toxicity an Issue for Some But Not All Combinations Too Many Combinations to Test in Adequately Powered Phase II Studies NeoAdjuvant Trials > Randomized Phase II > Phase III Forward Looking Perhaps Anti-PD-1 / PD-L1 is not Always The Best Immunological Partner Targeting the Tumor Microenvironment with IDO or CSF-1R Inhibition Targeting Treg Do Innate cytokines limit the activity of immunotherapy? Blocking IL-1, TNF-alpha, IL-6 + Immunotherapy

27 Drake Laboratory (Alumni) Tullia Bruno* Satoshi Wada Tim Harris Joe Grosso* Monica Goldberg* Nick Durham Chris Nirshl* Andrew Sharabi Tina Ceccato* Drake Laboratory (Current) Daisy Chen Chris Jackson Brian Francica Areli Lopez Allison Martin Ali Ghasmedzehah Areli Lopez Maria Carera Tom Nirschl Acknowledgements Urology Mo Allaf Mark Ball Mike Gorin Mike Johnson Phil Pierazio BMS Alan Korman Mark Selby Kent Thudium Nils Lonberg Maria Jure-Kunkel 043 ProstateTrial Win Gerritsen Howard Scher Eugene Kwon Patients and Families Pathology Angelo De Marzo Helen Fedor Alan Meeker Mike Haffner Funding Damon Runyon MRA NIH / NCI OneInSix PCF PCW Foundation Dept Urology BMS IIoN Slides / Collaboration David McDermott Hans Hammers Brian Rini

28 The JHU Immunotherapy Team

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