Immune Checkpoint Blockadeagainst Malignancy

BlockingSelf-inflictedInhibitions?

IGNORANT T CELL

Insufficient antigen/lack of co-stimulatory signals

ANERGIC T CELL

Unsuccessful stimulation/negative regulation

APOPTOTIC T CELL(DELETED)

Programmed cell death

NAIVE T CELL PRIMED T CELL EFFECTOR T CELL MEMORYT CELL:

Central memory cellEffector memory cellCD27

CD28HVEM

TCR

MHC-peptide

CD27LCD80/86LIGHT

CTLA-4B7-H4R

CD80/86B7-H4

PD-1B7-H4RB7-H1BTLA-4

B7-H1B7-DCB7-H4BTLA-4R

CD137OX40ICOSB7-H3R

CD137LOX40LB7hB7-H3

IL-15IL-7CD-137OX-40others

IL-12IFN-α

Glennie MBJCP 2013

Costimulatory and coinhibitory ligand receptor pairs that are amenable to manipulation with immunostimulatory mAbs.

Melero I et al. Clin Cancer Res 2013;19:997-1008©2013 by American Association for Cancer Research

PhosphatasesDeubiquitinases

Transcriptionfactors

UnknownsUnknownunknowns

CTLA-4

CD80

CD86

CD28

CTLA-4

+

-

A) COMPETITION B) NEGATIVE SIGNALING

D) T REG ACTIVATIONC) CD80/CD86 COOPTION BY TRANSCYTOSIS

Tivol EAImmunity1995

Heart

Pancreas

Kuehn HSScience 2014

Anti-CTLA-4Phase III clinical trialsRegistered for metastatic melanoma.Combines with vaccination preclinically.10-20% sustained responses in phase II30% incidence of moderate/severe autoimmunity

CTLA-4-/- dies because of multiorganlymphocyte infiltration

Response to Ipilimumab 10 mg/kg x 2 doses

No progression 5+ years

Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone1-yr 44% 46% 25%2-yr 22% 24% 14%

Ipilimumab Pattern of Response:Responses After the Appearance and Subsequent

Disappearance of New Lesions

3 mg/kg ipilimumab

Q3W X 4

Pre-treatment

Week 36: Still Regressing

Week 12: Progression

Week 20: Regression

New lesions

Source: 2008 ASCO Abstract #3020 Wolchok.

July 2006

irRC Identifies Survivors in Patients with Progressive Disease by mWHO

Pooled data from phase II studies CA184-008 and CA184-022:ipilimumab monotherapy 10 mg/kg (N=227)

Wolchok et al, Clin Cancer Res, 2009

Mocellin SBioch Bioph Acta 2013

Phase II Trial of Anti-CTLA-4 Human Monoclonal Antibody CP-675,206 in

Patients With Advanced HCC

Clinica Universidad de Navarra, Pamplona

Hospital Universitario Reina Sofía, Córdoba

Hospital Universitario 12 de Octubre, Madrid

Protocol code CT-2007-01EudraCT no. 2008-001177-15NCT Identifier NCT01008358Sponsor: University of Navarra, Pamplona, SpainPI: Prof. Jesus Prieto

Killing two birds with one stone

Tumor Response on Target Lesions

-80

-60

-40

-20

0

20

40

60

Antiviral EfficacySerum HCV Viral Load

1,00E+00

1,00E+01

1,00E+02

1,00E+03

1,00E+04

1,00E+05

1,00E+06

1,00E+07

1,00E+08

0 30 120 210 300 360 390 530

Copi

es/m

L

Days after initiation of therapy

Patients with virological follow-up longer than 1 month

rCore

0 30 120 210 300 3300

10

20

30

40

50

Days after treatment

SFC

rNS3

0 30 120 210 300 3300

20

40

60

Days after treatmentS

FC

rNS4

0 30 120 210 300 3300

50

100

150

Days after treatment

SFC

rNS5

0 30 120 210 300 3300

20

40

60

80

Days after treatment

SFC

pepP7

0 30 120 210 300 3300

10

20

30

40

50

Days after treatment

SFC

pepE2

0 30 120 210 300 3300

50

100

150

Days after treatment

SFC

pepE1

0 30 120 210 300 3300

50

100

150

Days after treatment

SFC

pepCore

0 30 120 210 300 3300

20

40

60

80

Days after treatment

SFC

pepNS5

0 30 120 210 300 3300

100

200

300

400

500

Days after treatment

SFC

pepNS4

0 30 120 210 300 3300

50

100

150

Days after treatment

SFC

pepNS3

0 30 120 210 300 3300

50

100

150

200

Days after treatment

SFC

pepNS2

0 30 120 210 300 3300

20

40

60

80

Days after treatment

SFC

*

*

*

Immunological OutcomesGlobal Changes in Anti-HCV Immune

Response

PD-1/PD-L1

Nirschl CJ Clin Cancer Res 2013

Nishimura HScience 2001

Riella LVAm J Transplant 2012

Dendriticcell

T cellTumor cell

MHC

PD-L1

MHCTCR

PD-L2

CD28 B7.1/2NFκB

Other

PI3K

Shp-2 Shp-2

IFNγ

IFNγR

Lymphocyte priming to tumor antigens

TCR

PD-L2

PD-1 PD-L1PD-1

Tumor-specific T cell recognition in the periphery

Role of the PD-1 pathway in suppressing anti-tumor immunity

(+)

(-)(-)

Annual Reviews

PD-L1 (B7-H1) Expression in Multiple Cancers

Source: Zou W. and Chen L. Nature Reviews Immunology. 2008;8:467-477. ND = Not determined.

Target PD-L1 Is Broadly Expressed in Human Cancer

31

Positive PD-L1 staining in lung cancer (NSCLC)(proprietary Genentech/Roche PD-L1 IHC)

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).

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

Momtaz PPharmacogen Pers Med2014

Months since treatment initiation

Ove

rall

surv

ival

(%) NSCLC 9.6 42 14

MEL 16.8 62 43

Med.OS % survival (months) 1 YR 2YR

0

100

80

60

40

20

03 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated88/129

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated60/107

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated15/34

0

100

80

60

40

20

(95% CI); (7.8, 12.4) (33, 51); (4, 24);pts at risk 43 5

(95% CI); (12.5, 31.6) (53, 72); (32, 53);pts at risk 55 26

(95% CI); (13.6, NE) (55, 86); (31 ,70);pts at risk 23 8

RCC >22 70 50

Duration of response in patients receiving nivolumab

Months since initiation of response

Prop

ortio

n pr

ogre

ssio

n-fr

ee

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33

NSCLC 22 21 16 14 12 8 5 2 2 1 1 0MEL 33 33 30 27 19 15 12 9 5 0 0 0RCC 10 10 10 9 5 3 2 2 2 1 0 0

No. at Risk

Med., mo. (95%CI)NSCLC (n=22) 17.0 ( 9.7 - NE) Melanoma (n=33) 24.0 (17.0 - NE)RCC (n=10) 12.9 (11.4 - NE)

Censored

NE, not estimable

Tissue distribution of the most frequent irAEs observed with immunostimulatory mAbs.

Melero I et al. Clin Cancer Res 2013;19:997-1008

©2013 by American Association for Cancer Research

SYNERGYsyn-ergos, συνεργός, meaning

'working together'.

α-OX40

Radiotherapy

Chemotherapy

Vaccination

T-reg depletion/inactivation

Adoptive T-cellimmunotherapy

–Clinical Standard–Clinical Trials–Preclinical Studies

Antiangiogenictherapy

α-TIM-3

α-LAG3

α-CTLA-4

α-CD137

α-PD1 α-PD-L1

α-CD40

Virotherapy

Clinical activity and safety of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination

with ipilimumab in patients with advanced melanoma

Jedd D. Wolchok,1Harriet 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,1William Feely,3 Quan Hong,3 Christine E. Horak,3 Alan J. Korman,4 Jon M. Wigginton,3

Ashok Gupta,3 and Mario Sznol2

1Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY; 2Yale University School of Medicine and Yale Cancer Center, New Haven, CT;

Bristol-Myers Squibb, 3Princeton, NJ and 4Redwood City, CA

40

Evaluating PD-L1 status as a candidate biomarker

Nivolumab monotherapy

(Grosso et al. ASCO 2013)

Combination nivolumab plus

ipilimumab

Sequenced nivolumab after

ipilimumab

3/21

7/17 9/226/13

1/13

4/8

_ _ _+ + +

Positivity rate = 45% (17/38, monotherapy), 37% (13/35, combination therapy), and 38% (8/21, sequenced therapy)

Strategies for immunotherapy combinations.

Melero I et al. Clin Cancer Res 2009;15:1507-1509

©2009 by American Association for Cancer Research

Antigenicity

MS Lawrence et al. Nature 000, 1-5 (2013) doi:10.1038/nature1221

Somatic mutation frequencies observed in exomes from 3,083tumour–normal pairs.

Mutational Landscape of Tumors According to Clinical Benefit from Ipilimumab Treatment.

Snyder A et al. N Engl J Med 2014;371:2189-2199

Association of a Neoepitope Signature with a Clinical Benefit from CTLA-4 Blockade.

Snyder A et al. N Engl J Med 2014;371:2189-2199

Nivolumab and NSCLC

Rizvi et al Science 2015

CD4

Tregs

MELANOMA

NSCLC

RENAL CELL CARCINOMA

HEAD AND NECK

BLADDER

DIGESTIVE TUMORS

HEMATOLOGICAL MALIGNCIES

…And a long listIncluding BREAST CANCER

.

. .