Immune Checkpoint Blockade against Malignancy. Blocking Self-inflicted Inhibitions?

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Augustus Henderson
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1 Immune Checkpoint Blockade against Malignancy Blocking Self-inflicted Inhibitions?

3 IGNORANT T CELL ANERGIC T CELL APOPTOTIC T CELL (DELETED) Insufficient antigen/ lack of co-stimulatory signals Unsuccessful stimulation/ negative regulation Programmed cell death NAIVE T CELL PRIMED T CELL EFFECTOR T CELL MEMORY CD27 CD28 HVEM CTLA-4 B7-H4R CD137 OX40 ICOS B7-H3R IL-12 IFN-α PD-1 B7-H4R B7-H1 BTLA-4 IL-15 IL-7 CD-137 OX-40 others T CELL: Central memory cell Effector memory cell TCR MHC -peptide CD27L CD80/86 LIGHT CD80/86 B7-H4 CD137L OX40L B7h B7-H3 B7-H1 B7-DC B7-H4 BTLA-4R

6 Glennie M BJCP 2013

7 Costimulatory and coinhibitory ligand receptor pairs that are amenable to manipulation with immunostimulatory mabs. Transcription factors Phosphatases Deubiquitinases Unknowns Unknown unknowns 2013 by American Association for Cancer Research Melero I et al. Clin Cancer Res 2013;19:

8 CTLA-4

9 CD80 CD CD86 CTLA-4

10 A) COMPETITION B) NEGATIVE SIGNALING C) CD80/CD86 COOPTION BY TRANSCYTOSIS D) T REG ACTIVATION

11 Heart Pancreas Tivol EA Immunity 1995

12 Kuehn HS Science 2014

incidence of moderate/severe autoimmunity

13 Anti-CTLA-4 Phase III clinical trials Registered for metastatic melanoma. Combines with vaccination preclinically % sustained responses in phase II 30% incidence of moderate/severe autoimmunity CTLA-4-/- dies because of multiorgan lymphocyte infiltration

14 Response to Ipilimumab 10 mg/kg x 2 doses No progression 5+ years

15 Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%

16 Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-treatment July 2006 Week 12: Progression 3 mg/kg ipilimumab Q3W X 4 New lesions Week 20: Regression Week 36: Still Regressing Source: 2008 ASCO Abstract #3020 Wolchok.

17 irrc Identifies Survivors in Patients with Progressive Disease by mwho Pooled data from phase II studies CA and CA : ipilimumab monotherapy 10 mg/kg (N=227) Wolchok et al, Clin Cancer Res, 2009

18 Mocellin S Bioch Bioph Acta 2013

2008-001177-15 NCT Identifier NCT01008358 Sponsor: University of Navarra, Pamplona, Spain PI:

19 Phase II Trial of Anti-CTLA-4 Human Monoclonal Antibody CP-675,206 in Patients With Advanced HCC Protocol code CT EudraCT no NCT Identifier NCT Sponsor: University of Navarra, Pamplona, Spain PI: Prof. Jesus Prieto Clinica Universidad de Navarra, Pamplona Hospital Universitario 12 de Octubre, Madrid Hospital Universitario Reina Sofía, Córdoba

20 Killing two birds with one stone

21 Tumor Response on Target Lesions

22 1,00E+08 1,00E+07 1,00E+06 Antiviral Efficacy Serum HCV Viral Load Patients with virological follow-up longer than 1 month Copies/mL 1,00E+05 1,00E+04 1,00E+03 1,00E+02 1,00E+01 1,00E Days after initiation of therapy

23 Immunological Outcomes Global Changes in Anti-HCV Immune SFC rcore SFC Response rns3 rns4 150 * SFC * SFC rns Days after treatment Days after treatment Days after treatment Days after treatment pepcore pepe1 pepe2 pepp SFC * SFC SFC SFC Days after treatment Days after treatment Days after treatment Days after treatment pepns2 pepns3 pepns4 pepns SFC SFC SFC SFC Days after treatment Days after treatment Days after treatment Days after treatment

24 PD-1/PD-L1

25 Nirschl CJ Clin Cancer Res 2013

26 Nishimura H Science 2001

27 Riella LV Am J Transplant 2012

28 Role of the PD-1 pathway in suppressing anti-tumor immunity IFNγ Tumor cell IFNγR MHC PD-L2 TCR (-) Shp-2 (+) PI3K NFκB Other T cell (-) Shp-2 TCR MHC CD28 B7.1/2 PD-L2 Dendritic cell PD-L1 PD-1 PD-1 PD-L1 Tumor-specific T cell recognition in the periphery Lymphocyte priming to tumor antigens

29 Annual Reviews

30 PD-L1 (B7-H1) Expression in Multiple Cancers Source: Zou W. and Chen L. Nature Reviews Immunology. 2008;8: ND = Not determined.

Target PD-L1 Is Broadly Expressed in Human Cancer Positive PD-L1 staining in lung cancer (NSCLC) (proprietary Genentech/Roche PD-L1 IHC) Tumor Type Estimated PD-L1 Prevalence, % * NSCLC (SCC) 50%

31 Target PD-L1 Is Broadly Expressed in Human Cancer Positive PD-L1 staining in lung cancer (NSCLC) (proprietary Genentech/Roche PD-L1 IHC) Tumor Type Estimated PD-L1 Prevalence, % * NSCLC (SCC) 50% NSCLC (adeno) 45% Colon 45% Melanoma 40% Renal 20% Nearly all human cancer types can express PD-L1 High sensitivity and specificity in FFPE samples * Surgical tumor specimens (internal Genentech data). NSCLC samples include collaboration with Ignacio Wistuba (MD Anderson) and David Shames (Genentech). 31

32 Momtaz P Pharmacogen Pers Med 2014

33 Overall survival (%) Died/treated 88/ Died/treated 60/107 Died/treated 15/ Months since treatment initiation Med.OS % survival (months) 1 YR 2YR NSCLC (95% CI); (7.8, 12.4) (33, 51); (4, 24); pts at risk 43 5 MEL (95% CI); (12.5, 31.6) (53, 72); (32, 53); pts at risk RCC > (95% CI); (13.6, NE) (55, 86); (31,70); pts at risk 23 8

34 Duration of response in patients receiving nivolumab Proportion progression-free Med., mo. (95%CI) NSCLC (n=22) 17.0 ( NE) Melanoma (n=33) 24.0 ( NE) RCC (n=10) 12.9 ( NE) Censored No. at Risk Months since initiation of response NSCLC MEL RCC NE, not estimable

35 Tissue distribution of the most frequent iraes observed with immunostimulatory mabs. Melero I et al. Clin Cancer Res 2013;19: by American Association for Cancer Research

36 SYNERGY syn-ergos, συνεργός, meaning 'working together'.

38 Chemotherapy Virotherapy Vaccination α-cd137 Radiotherapy α-ox40 α-pd1 α-pd-l1 α-ctla-4 Adoptive T-cell immunotherapy α-tim-3 α-cd40 α-lag3 Antiangiogenic therapy T-reg depletion/ inactivation Clinical Standard Clinical Trials Preclinical Studies

39 Clinical activity and safety of nivolumab (anti- PD-1, BMS , ONO-4538) in combination with ipilimumab in patients with advanced melanoma Jedd D. Wolchok, 1 Harriet Kluger, 2 Margaret K. Callahan, 1 Michael A. Postow, 1 RuthAnn Gordon, 1 Neil H. Segal, 1 Naiyer A. Rizvi, 1 Alexander M. Lesokhin, 1 Kathleen Reed, 2 Matthew M. Burke, 2 Anne Caldwell, 2 Stephanie A. Kronenberg, 1 Blessing U. Agunwamba, 1 William Feely, 3 Quan Hong, 3 Christine E. Horak, 3 Alan J. Korman, 4 Jon M. Wigginton, 3 Ashok Gupta, 3 and Mario Sznol 2 1 Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Yale University School of Medicine and Yale Cancer Center, New Haven, CT; Bristol-Myers Squibb, 3 Princeton, NJ and 4 Redwood City, CA

40 Evaluating PD-L1 status as a candidate biomarker 7/17 9/22 6/13 4/8 3/21 1/13 _ Nivolumab monotherapy (Grosso et al. ASCO 2013) Combination nivolumab plus ipilimumab Sequenced nivolumab after ipilimumab Positivity rate = 45% (17/38, monotherapy), 37% (13/35, combination therapy), and 38% (8/21, sequenced therapy) 40

41 Strategies for immunotherapy combinations. Melero I et al. Clin Cancer Res 2009;15: by American Association for Cancer Research

42 Antigenicity

43 Somatic mutation frequencies observed in exomes from 3,083 tumour normal pairs. MS Lawrence et al. Nature 000, 1-5 (2013) doi: /nature1221

44 Mutational Landscape of Tumors According to Clinical Benefit from Ipilimumab Treatment. Snyder A et al. N Engl J Med 2014;371:

45 Association of a Neoepitope Signature with a Clinical Benefit from CTLA-4 Blockade. Snyder A et al. N Engl J Med 2014;371:

46 Nivolumab and NSCLC Rizvi et al Science 2015

50 CD4 Tregs

51 And a long list Including BREAST CANCER... MELANOMA NSCLC RENAL CELL CARCINOMA HEAD AND NECK BLADDER DIGESTIVE TUMORS HEMATOLOGICAL MALIGNCIES

Understanding Checkpoint Inhibitors: Approved Agents, Drugs in Development and Combination Strategies. Michael A. Curran, Ph.D.

Understanding Checkpoint Inhibitors: Approved Agents, Drugs in Development and Combination Strategies Michael A. Curran, Ph.D. MD Anderson Cancer Center Department of Immunology Disclosures I have research