Download Immune Checkpoint Inhibitors

Immune Checkpoint Inhibitors
Paul Lorigan
University of Manchester
Christie NHS Foundation Trust
Manchester
Immune System and Types of Cancer Therapy
6. T cell therapy
Tumour
CTL
5. Blocking Inhibitory
signals - PD-1, PDL-1, LAG-3
Stimulating T-cells: OX40, CD137
1. Vaccine
APC
T cell
T regulatory
Cells
4. Modulate Regulatory Cells
IL-2
T cell
IL-2
2. Cytokine: e.g IL-2
3. Blocking inhibitory signals e.g. CTLA-4
T cells Enable the Immune System to
Detect and Destroy Tumour Cells
1. Antigens are released by tumour cells
and captured by dendritic cells.
Dendritic cell
Naive T cell
TUMOUR
2. Dendritic cells
activate naïve
T cells in
lymph nodes.
LYMPH
NODE
4. T cells kill tumour cells through
the release of lytic enzymes or
induction of apoptosis.
Activated T cell
3. Activated T cells migrate
back to the tumour.
May KF Jr et al. Cancer Immuno. 2013.
T-Cell Activity Is Regulated By Immune
Checkpoints to Limit Auto-immunity
Dendritic cell
Inactivated T
cell
TUMOUR
-
Checkpoints
Checkpoints
Inactivated T
cell
-
LYMPH
NODE
Activated T cell
Pardoll DM. Nat Rev Cancer. 2012
Blocking CTLA-4 Ligation Augments
Immune Responses
1. Co-stimulation via CD28
ligation transduces T cell
activating signals
2. CTLA-4 ligation on activated
T cells down-regulates T cell
responses
T cell Activation
T cell
3. Blocking CTLA-4 ligation
enhances T cell responses
T cell Inactivation
T cell Activation
T cell
T cell
CTLA-4
CTLA-4
TCR
MHC
TCR
CD28
B7
APC
MHC
CTLA-4
TCR
MHC
CD28
CD28
B7
APC
B7
APC
Anti-CTLA4 mAb
(MDX-010)
Pooled Analysis of phase I-III Studies of
ipilimumab in 2800 stage IV Melanoma Patients
Anti CTLA-4 Expands Teff And Treg Cells In Lymph Node While
Simultaneously Depleting Intratumoural Treg Cells
By ADCC
Furness et al, Trends in Immunology 2014
Astx, Cambridge. September 2015
How Does CTLA4 Blockade Lead To Antitumour Immune Response?
1. Priming of tumour-reactive T cells
– Against shared tumour associated antigens
– Against mutated (neo) antigens
2. Depletion of regulatory FoxP3+ T cells from
the tumour microenvironment
– Fc dependent T-reg depletion?
Simpson et al. JEM 2013
Targeting The Immune Checkpoints
Effector phase
Priming phase
Dendritic cell
T-cell
T-cell
Lymph
node
MHC
Cancer
cell
TCR
Peripheral
tissue
TCR
MHC
Activation signals
B7
CD28
Negative regulation
PD1
PD-L1
Inhibitory signals
B7
Antibody
CTLA-4
Antibody
Antibody
Ribas A, et al. NEJM 2012
Nivolumab vs DTIC in BRAF WT patients
Nivolumab
Eligible patients
with
unresectable
stage III or IV
melanoma
(n=418)
•BRAF wild-type
•Treatment-naïve
3 mg/kg IV Q2W
+
Placebo
IV Q3W
Double-blind
R
1:1
Placebo
IV Q2W
+
Dacarbazine
Stratified by:
•PD-L1 status†
•M-stage
†PD-L1
n=210
(206 treated)
1000 mg/m2 IV Q3W
n=208
(205 treated)
Treat until
progression* or
unacceptable
toxicity
Primary endpoint:
•OS
Secondary
endpoints:
•PFS
•ORR
•PD-L1 correlates
positive: ≥ 5% tumour cell surface staining.
*Patients
may be treated beyond initial RECIST v1.1-defined progression if considered by the investigator to be
experiencing clinical benefit and tolerating study drug.
Immunotherapies: An Overview. London
2015
Overall Survival
70.7%
57.7%
Median OS,
mo. (95% CI)
46.3%
26.7%
• Minimum survival follow-up of 15.1 months
HR (95% CI)
NIVO (N = 210)
DTIC (N = 208)
NR (23.1, NR)
11.2 (9.6, 13.0)
0.43 (0.33, 0.57); P <0.001
Role of the Immune System in Cancer and the Process of
Immunoediting
•
Immunoediting describes the contrasting role of the immune system in
protecting against tumour development and promoting tumour growth
Elimination
Cancer immunosurveillance
•
•
CD8+ T cell
Effective antigen
processing/presentation
Effective activation and
function of effector cells
‒ e.g. T cell activation
without co-inhibitory
signals
CD4+ T cell
Equilibrium
Escape
Cancer dormancy
•
•
•
Genetic instability
Tumour
heterogeneity
Immune selection
Cancer progression
•
Tumours avoid elimination
through the outgrowth of
tumour cells that can
suppress, disrupt, or
‘escape’ the immune
system
NK cell
Treg
Tumour cells
Normal cells
Vesely MD, et al. Ann Rev Immunol 2011;29:235–71
Emerging Hallmarks of Cancer: Avoiding Immune Destruction
Adapted from Hanahan D, et al. Cell 2011;144:646–74
Mutational Burden
Alexandrov Nature 2013
Astx, Cambridge. September 2015
Neoantigen Specific T Cells In Patient Responding To
Ipilimumab
• WES of tumour and normal tissue to
identify tumour-specific mutations
• Filter for gene expression using
RNAseq
• Prediction for proteosomal
processing and HLA Class I binding
• Pepetides synthesised, bound to
HLA multimers, and exposed to patient
derived TILs
• Mutation ATR protein kinase
mutation that signals DNA damage
identified,
• Showed 5-fold increase in
neoantigen-specific T cell response on
treatment
Van Rooij et al JCO 2013
Astx, Cambridge. September 2015
Predicting Response To CTLA-4
Snyder NEJM 2014
Astx, Cambridge. September 2015
PD-L1 Expression and Relationship With Response
Presented By Adil Daud at 2015 ASCO Annual Meeting
Immune Resistance
D Pardoll, Nat Rev 2012
CD8+ Cells Predict Response To
PD-1 Inhibitors
Tumeh et al. Nature 2014
Astx, Cambridge. September 2015
Co-localisation Of PD-1 And PD-L1 Positive
Cells Predicts Response – Proximity Analysis
Tumeh et al. Nature 2014
Co-localisation Of PD-1 And PD-L1
Positive Cells Predicts Response
Tumeh et al. Nature 2014
Presence of Tregs and expression of PD-L1 and IDO are associated with a CD8+ T cell infiltrate
PD-L1
•
•
•
•
•
Inducible
Expressed on many cell types in TME
Majority cells in body have IFN receptors
Tumours respond to IFN by upregulating PD-L1
Inflamed tumour microenvironment
advantageous, until treat with PD-1
• JAK 1 and 2 required for response to IFN
• LOF mutations mean won’t respond to anti-PD-1
Hypotheses for molecular mechanisms to explain the T cell-inflamed versus non-inflamed tumor microenvironments
Malignant melanoma samples from TCGA segregated based on T cell-inflamed gene signature
Expression of differentiation antigens and cancer-germline antigens is comparable in T cell signature-high versus -low patients
Overall mutational load (non-synonymous mutations) is comparable in T cell signature-high versus -low samples
T cell signature-high and -low patients have equal patterns of predicted HLA-A0201 binding peptides
48% of non-T cell-inflamed tumors show evidence of active b-catenin signaling, which inhibits immune cell recruitment into tumor site
Astx, Cambridge. September 2015
Genetic background:
•MHC
•DNA repair system
•Immune background
Tumor-specific:
•Mutations, Neoantigens
•DNA repair capacity
•Immune targets: PD1, PDL-1,..
Genetic background:
•MHC
•DNA repair system
•Immune background
Tumor-specific:
•Mutations, Neoantigens
•DNA repair capacity
•Immune targets: PD1, PDL-1,..
Immune landscape :
•Immunoscore: CTL,
repertoire, Treg, Bcells,
Tfh, MDSC,…
•Immune biomarkers: PD1,
PDL-1, Lag-3, …
Genetic background:
•MHC
•DNA repair system
•Immune background
Microbiome
•Gut
•Skin…
Commensal bacteria control
cancer response to therapy
•Lida et al Science 2013
•Viaud et al Science 2013
Tumor-specific:
•Mutations, Neoantigens
•DNA repair capacity
•Immune targets: PD1, PDL-1,..
Immune landscape :
•Immunoscore: CTL,
repertoire, Treg, Bcells,
Tfh, MDSC,…
•Immune biomarkers: PD1,
PDL-1, Lag-3, …
Anti-Tumour Activity of Anti-CTLA-4 and anti-PD-1 Antibodies in Murine Tumour Models
0/12
tumour-
free
3000
2000
1000
0
0
10
20
30
Days
40
Anti-CTLA-4
3000
50
0/12
tumour-
free
2000
1000
0
0
10
20
30
Days
40
50
Tumour volume (mm3/2)
mIgG
Tumour volume (mm3/2)
Tumour volume (mm3/2)
Tumour volume (mm3/2)
MC38 colon cancer. Antibody treatment only
Anti-PD-1
1/12
tumour-
free
3000
2000
1000
0
0
10
20
30
Days
40
50
Anti-PD-1 + anti-CTLA-4
3000
2000
9/12
tumourfree
1000
0
0
10
20
30
Days
40
50
Selby M, et al. J Clin Oncol 2013;31(suppl): abstract 3061
T cell: APC interface
• Various costimulatory and coinhibitory molecules contribute to maintenance of immune
homeostasis
• CTLA-4 is key mediator of immune tolerance
Peggs KS, et al. Clin Exp Immunol 2009;157:9–19