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
.
. .
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