Immunotherapy in metastatic colon cancer

IMMUNOTHERAPY IN COLON
CANCER
Waseem Abbas
Medical Oncologist @ MAX CANCER CENTRE SHALIMARBAGH

Fluorinated Pyrimidines, A New Class ofTumour-
Inhibitory Compounds
 Nature-1957
 Rat hepatomas use uracil more efficiently than non-
malignant tissue

T-STAGE N-STAGE M-STAGE
Tumor cell
extension
and invasion
CD3+ T cells CD8+ T cells Density Location (CT, IM)Immunoscore
Host immune
response
Mucinous CCS1
CCS2Medullary
Adeno. NOS
Serrated
Signet ring cell
Enterocyte
Goblet-like
Transit-amplifying-S
Inflammatory
Stem-like
CIN
MSI
CIMP CCS3Transit-amplifying-R
BRAF
APC
KRAS
TP53
Morphology Cell of origin Molecular pathway Mutation status Gene expression
Tumor cell
characteristics
Ways to classify
CTNNB1
Micropapillary
Cribriform comedo
-type
Galon et al. J Pathol. 2014
Colorectal cancer classifications

Memory T cells, in particular, TEM correlate with the absence
of early-metastatic invasion, and improved clinical outcome
in colorectal carcinoma.
Pagès F, et al. N Engl J Med. 2005
Pagès F & Galon J. N Engl J Med. 2006
*

 Quantification of immune cell densities (6640 IHC) revealed the major
positive role of cytotoxic and memory T cells for patient’s survival
A Novel Paradigm for Cancer
Galon J et al. Science 2006
ImmunoscoreImmune contexture
The foundation a new concept
Cohort 1:
patients
n= 415
Validation cohorts: n= 188 patients

COX multivariate analysis (OS) in all stages I, II, III patients
Parameter HR P value
• T-stage
• N-stage
• Differentiation
• Immunoscore
1.2 0.25
1.4 0.15
1.1 0.84
1.9 0.00001
Novel Paradigm
Galon J et al. Science 2006
Galon J et al. Cancer Res. 2007
“Contexture: the act of assembling parts into a whole; an arrangement of interconnected parts”
“Immune Contexture” : nature, immune functional orientation, density, and
location within distinct tumor regions, of a natural in situ immune reaction
Invasive margin (IM)
tumor
tumor
immune
immune
Center of the tumor (CT)

Prolonged survival in patients with high Immunoscore (Im)
based on the evaluation of CD45RO-CT/IM and CD8-CT/IM
Mlecnik et al. J Clin Oncol 2011
Survival (months)
P<0.0001
Disease-FreeSurvival(%)
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180
Im4
Im3
Im2
Im1
Im0
AJCC/UICC-Stage I-III
Im4
Im3
Im2
Im1
Im0
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180
Survival (months)
P<0.0001
AJCC/ UICC-Stage I-IV

 Tumor progression, invasion and recurrence are dependent on the immune contexture
and Immunoscore
 Pre-existing immunity is determining the fate and survival of the patient
Galon J et al. Science 2006. Mlecnik B et al. JCO 2011
Cox Multivariate analysis including Immunoscore

Immune
Functional
orientation
IFNG GZMA
IL12 GZMB
TBX21 GZMH
IRF1 PRF
STAT1 GLNY
MADCAM1
ICAM1
VCAM1
ITGAE
Quantification (cells/mm2)
Adaptive immunity, cytotoxic, memory T cells
Tumor center, Margin, Tertiary lymphoid ilets
Immune contexture
Immunologic
Constant of
Rejection
(other diseases)
CX3CL1
CXCL9
CXCL10
CCL5
CCL2
Location
Immunoscore
The overlap between the immune contexture, the
immunologic constant of rejection and the Immunoscore
CXCL13
IL21, IL15
Galon J et al.
Immunity 2013
-> ImmunoSign

immune signatures
NON-Immune signatures
Prognostic Predictive
The overlap between prognostic, predictive and mechanistic
Mechanistic
IMMUNE signatures
Prognostic
Mechanistic
Predictive
ICR
Immune
contexture
Galon J et al. Immunity 2013
Immunoscore
Th1
Cytotoxicity
Chemokines
Cytokines
Adhesion

• Evolution of the tumor microenvironment with tumor progression?
• Immune escape mechanisms in human tumors?
Understanding the evolution of the immune response
with tumor progression using systems biology
-> Spatio-temporal dynamics
of the immune response with tumor progression
Bindea G et al. Immunity, 2013
Tis
T1 T2 T3 T4
∆ ∆ ∆ ∆
T-Stage

CD3
FoxP3
CD20
CD8extra
CD8intra
CD68intra
CD68
CD45RO
PDPN
CD57
CXCR5
IL17
Tryptase
Granulocyte
IL17
ENG
IL3RA
IL3RA
Tryptase
CD1A
CD3
FoxP3
CD20
CD8extra
CD8intra
CD68intra
CD68
CD45RO
PDPN
CD57
CXCR5
Granulocyte
ENG
CD1A
CD8
CD8
x-y-Force Directed Topology
Center of the tumor
(CT)
Cell density
Cell density
(cells/mm2)
tumor progression
with tumor progression : The immune landscape
Bindea G et al. Immunity 2013
TFH
B-cells

CD3
FoxP3
CD20
CD20
CD8extra
CD8intra
CD8intra
CD68intra
CD68
CD45RO
CD45RO
PDPN
CD57
CXCR5
Granulocyte
IL17
ENG
Tryptase
IL3RA
CD1A
CD3
FoxP3
CD20
CD8extra
CD8intra
CD68intra
CD68
CD45RO
PDPN
CD57
CXCR5
Granulocyte
IL17
ENG
Tryptase
IL3RA
CD1A
CD8
CD8
Cell density
Impact on DFS
x-y-Force x-yD-
Fiorerccteed
DirTeocpteodlogy
TopoloIngvyasive margin
(IM)
Center of the tumour (CT)
CD3
FoxP3
CD8extra
CD68intra
CD68
PDPN
CD57
CXCR5
TFH
Granulocyte
IL17
ENG
Tryptase
IL3RA
CD1A
CD3
FoxP3
CD20
CD8extra
CD8intra
CD68intra
CD68
CD45RO
PDPN
CD57
CXCR5
Granulocyte
IL17
ENG
Tryptase
IL3RA
CD1A
CD8
CD8
Center of the tumor (CT)
Hazard ratio
with tumor progression : The immune landscape
Bindea G et al. Immunity 2013
tumor recurrence
Good
Bad
B-cells
T 17H

?
Metastasis (M1) ?
 Early-Metastasis (venous emboli, perineural invasion)
 Synchronous Metastasis (M1)
 Metachronous Metastasis (recurrence)
Mlecnik et al. Science Transl Med. 2016
What drives metastasis?

March 15th, 2016
TCGA CRC cohort:
Inserm cohort:
n=270 patients
n=689 patients

Patients with MSI-H have multiple Frameshift mutations
(Fsmut)
MSS MSI-H
cohort 1
cohort 2
0
ExomeSeq Multiplex FSmut validation
Mlecnik et al. Immunity 2016

Most of over-expressed genes in MSI-H patients correspond to
immune-related genes
Gene functions and gene distribution analysis using ClueGO software

Patients with MSI-H have increased intratumoral T-cell
proliferationTriple immunofluorescence quantification in situ
Increased CD3+Ki67+ cells in the center, invasive margin and tertiary lymphoid structures in patinets with MSI-H

 Most MSI and a subgroup of MSS patients have high intratumoral adaptive immune gene expression
 Functional effector anti-frameshift mutation CTLs kill tumor cells in MSI patients
 Genetic evidence of immunoediting in human CRC, in particular for MSI patients
 Immunoscore gives an indicator of tumor recurrence and survival beyond MSI staging

Patient 1 (weak)
CD3
Tumor
Patient 2 (moderate) Patient 3 (strong)
How to explain “Hot” and “Cold” immune infiltrated tumors ?
Median OS < 2 years
(death)
4.9 years > 15 years
Im0 Im2 Im4Immunoscore
CD3/CD8
Center/Margin

Mechanisms associated with T cells infiltration
Attraction Adhesion
MADCAM1
VCAM1
ICAM1
T cells
IL15
TH1
Cytotoxic
Memory
T cells
CXCL9
CXCL10
CCL2
CCL5
CX3CL1 CXCL13
TFH
B cells
Mlecnik et al. Gastroenterology 2010
Bindea et al. Immunity 2013
Local lymphocyte
proliferation
Mlecnik et al. Science Transl Med 2014

Prognostic importance of the in situ immune reaction in
patients with early-stage (Stage I/II) colorectal cancer
Pagès F et al. J. Clin. Oncol. 2009
Stage I cancer
CD45ROCT/IM CD8CT/IM P< .0001
Stage II cancer
100
80
60
40
20
0
0 25 50 75 100 125 150175 200
225
Survival (months)
Im4
Im3
Stage I
patients
Im1-2
Im0
0
20
40
60
80
100
0 25 50 75 100 125 150175 200 225
Survival (months)
Im4
Im3
Stage II
patients
Im1-2
Im0
P< .0001CD45ROCT/IM CD8CT/IM

THE IMMUNOSCORE
AS A NEW POSSIBLE
APPROACH IN
THE
CLASSIFICATION OF
CANCERNaples, Italy, Feb 2012 Organizer: P Ascierto, J. Galon, Principal investigator: J. Galon
Immunoscore steering committee: B. Fox, F. Marincola, C. Bifulco, P. Ascierto, J. Galon
Galon J et al. J. Transl. Med. 2012
Galon J et al. J. Pathol. 2014

IMMUNOSCORE®
Faisability
IHC automate High-resolution
scanner
whole slide quantification
Digital pathology
-> Conceptual and technological challenge
Immunoscore
Galon J et al. J. Transl. Med. 2012
Galon J et al. J. Pathol. 2014
-> Standardized Operating Procedure
-> Today’s tools for modern pathologists

Immunoscore in Colon Cancer:
Pt Population
Characteristics
Training Set
(n = 700)
Internal
Validation Set
(n = 636)
External
Validation Set
(n = 969)
Median age, yrs 68.3 (±12.6) 68.3 (±12.2) 68.2 (± 32.7)
Male, n (%) 346 (49.4) 339 (53.3) 497 (51.3)
T stage, n (%)
 T1
 T2
 T3
 T4
37 (5.3)
109 (15.6)
452 (64.6)
102 (14.6)
34 (5.3)
97 (15.3)
427 (67.1)
78 (12.3)
32 (3.3)
153 (15.8)
635 (65.5)
149 (15.4)
N stage, n (%)
 N0
 N1
 N2
508 (73.4)
124 (17.9)
60 (8.7)
482 (76.3)
107 (16.9)
43 (6.8)
608 (64.1)
223 (23.5)
117 (12.3)
Median lymph nodes, n 22.1 (±15.2) 21.8 (±16.9) 16.4 (±11.8)
Proximal colon cancer, n (%)
Distal colon cancer, n (%)
Missing, n (%)
349 (49.9)
349 (49.9)
2 (0.3)
307 (48.3)
327 (51.5)
1 (0.2)
527 (54.9)
431 (44.9)
2 (0.2)
Galon J, et al. ASCO 2016. Abstract 3500.

Characteristics Training Set
Internal
Validation Set
External
Validation Set
Time to end of follow-up
 Median survival, mos
 5-yr survival rate, %
143.6
(127.3-162.2)
74.9
(71.6-78.2)
180.7
(147.7-197.6)
77.8
(74.5-81.1)
160.1
(124.5-191.4)
68.8
(65.6-72.0)
Recurrence-free survival time
 Median survival, mos
 5-yr survival rate, %
122.3
(107.6-132.8)
68.3
(64.7-71.9)
140.2
(116.6-150.4)
71.3
(67.6-75.0)
95.1
(80.0-106.9)
58.3
(54.9-61.8)

Time to Recurrence, Training Set
Outcome
Training Set
High Intermediate Low
Primary objective (high/low):
5-yr time to recurrence, % (95% CI)
67.3
(59.4-76.2)
-- 85.3
(82.1-88.6)
HR (95% CI) 0.41 (0.28-0.61)
P value
C-index
< .0001
0.60
Secondary objective (high/int/low):
67.3
(59.4-76.2)
81.9
(77.7-86.3)
92.3
(88.2-96.6)
HR (95% CI)
Int vs high: 0.51 (0.34-0.77)
Low vs high: 0.19 (0.10-0.37)
P value
C-index
< .0001
0.64

Secondary Objectives Efficacy
EndpointsOutcome High Intermediate Low
69.0
(65.2-72.9)
80.6
(78.3-83.0)
88.9
(86.3-91.6)
HR (95% CI)
P value
Int vs high: 0.58 (0.48-0.71)
Low vs high: 0.29 (0.21-0.38)
< .0001
5-yr DFS, % (95% CI)
57.6
(53.8-61.7)
69.2
(66.6-71.9)
75.4
(72.0-79.0)
HR (95% CI)
P value
Int vs high: 0.69 (0.60-0.80)
Low vs high: 0.52 (0.43-0.62)
< .0001
5-yr OS, % (95% CI)
66.9
(63.4-70.7)
77.3
(75.0-79.7)
81.5
(78.5-84.6)
HR (95% CI)
P value
Int vs high: 0.73 (0.63-0.85)
Low vs high: 0.59 (0.49-0.71)
< .0001

Deciphering the tumor immune microenvironment:
Clinical implications
CD3
Tumor
Clinical implications
Predictions Response to immunotherapies
(CTLA4, PD1, PDL1, …)
“Cold” Tumor
I 0
“Hot” Tumor
I 4
Need T-cell priming
Cancer vaccine
CAR-T cells
But it is not as simple since biology is complex and is not dichotomized in good & bad

Pembrolizumab (Anti–PD-1) in MMRD CRC:
Study Design
 Eligibility for cohorts A and B:
 Metastatic or locally advanced CRC, with or
without MMRD (defined as: deficiency in MLH1,
MSH2, MSH6 or PMS2 by IHC, or MSI in ≥ 2 loci
by PCR)
 ≥ 2 previous cancer therapy regimens
 ECOG PS ≤ 1
 No previous checkpoint inhibitor therapy
 Treatment: pembrolizumab 10 mg/kg Q2W
 MMR testing using standard PCR-based assay
for detection of MSI
 Current report: updated data from cohort A3
Cohort A (n = 28)
MMRD CRC
Cohort B (n = 25)
MMRP CRC
Cohort C (n = 30)
MMRD non-CRC
Le DT, et al. ASCO 2016. Abstract 103.

Pembrolizumab in MMRD CRC: Efficacy
Outcome
MMRD CRC
(n = 28)
MMRP CRC
(n = 25)
Median follow-up, mos 9.3 6
ORR, % (95% CI) 57 (39-73) 0 (0-13)
Response, %
 CR
 PR
 SD (Wk 12)
 PD
 NE (no 12-wk scan)
11
46
32
4
7
0
0
16
44
40
Disease control rate, %
(95% CI)
89 (73-96) 16 (6-35)
Median PFS, mos NR 2.3
Median OS, mos NR 5.98

Pembrolizumab in MMRD CRC: OS and PFS
OS(%)
PFS(%)
Mos
MMRD
(mOS: NR)
OS PFS
10
0
50
0
0 3 6 12 15 1
8
21 24 27 30
MMRP
(mOS: 5.98 mos)
9
Mos
MMRD
(mPFS: NR)
10
0
50
0
0 3 6 12 15 1
8
21 24 27 30
MMRP
(mPFS: 2.3 mos)
9

Pembrolizumab in MMRD CRC: Duration of
Disease Control
 Complete and durable responses observed in > 50% of
pts with MMRD CRC
125
75
50
25
0
-25
-50
-75
-100
ChangeFromBaseline(%)
-125
100
365 73
0
MMRP CRC
MMRD CRC

Phase II CheckMate-142: Nivolumab +
Ipilimumab in MSI-H CRC
 Primary endpoint: ORR per investigator (RECIST 1.1)
 Secondary endpoint: ORR per IRC
 Exploratory endpoints: safety, tolerability, PFS, OS, biomarkers
Nivo 3
mg/kg
Q2W
(n = 19)
1st:
mStage 1
≥
7/19
Respon
ses ≥
7/1
9
MSI-H
CONTINUE
Nivo 3 mg/kg
Q2W
(n = 19 + 29 add’l
pts)
3rd:
mStage 2
• Nivo 3 mg/kg + Ipi
1 mg/kg (Q3W x 4)
• Then Nivo 3 mg/kg
(Q2W)
(n = 19 + 29 add’l
pts)
4th: cStage
2*
Second-line
CRC MSI-H; ≥
1 prior
treatment for
metastatic
disease;
≥ 1 target
lesion; ECOG
PS: 0-1
(N = 120)
3-
6/19
Nivo 3 mg/kg
Nivo 3 mg/kg
+ Ipi 1 mg/kg
(Q3W x 4)
Then Nivo 3
mg/kg (from
W13, Q2W)
(n = 19)
2nd:
cStage 1
Respon
ses
Respon
ses
*Currently
enrolling
Overman M, et al. ASCO 2016. Abstract 3501.

Nivolumab + Ipilimumab in MSI-H Colon
Cancer: ORR per Investigators
Nivolumab 3 mg/kg + Ipilimumab
1 mg/kg100
0 6 12182430364248546066727884
75
50
25
0
-25
-50
-75
-100
Wks
PercentChangeFromBaseline
Off treatment
Nivolumab +
ipilimumab
treatment
ongoing
First occurrence of new l
CR or PR
Response
Nivolumab 3
mg/kg +
Ipilimumab 1
mg/kg (n = 27*)
ORR, n (%) [95%
CI]
 CR
 PR
 SD
 PD
 Unable to
determine
9 (33.3) [18.6-
50.9]
0
9 (33.3) [16.5-
54.0]
14 (51.9)
3 (11.1)
0
Median time to
response, mos
(range)
2.73 (1.2-6.9)
Median duration
of response, mos
(range)
NE (NE-NE)
*Pts with ≥ 12 wks of follow-up.

Nivolumab + Ipilimumab in MSI-H Colon Cancer:
Best Reduction in Target Lesion Size
*Confirmed responses.
56% pts with reduction 81% pts with reduction
Nivolumab 3 mg/kg +
Ipilimumab 1 mg/kg
Nivolumab 3 mg/kg100
75
50
25
0
-25
-50
-75
-100
BestReductionFromBaseline
inTargetLesion(%)
Pts
100
75
50
25
0
-25
-50
-75
-100
BestReductionFromBaseline
inTargetLesion(%)
Pts
***
*****
****
**
****
*
**% change truncated to 100%

Nivolumab70 19 13 9 5 0
Nivo + Ipi30 21 7 0 0 0
Pts at Risk, n
0
13 1
0
0 3 6 9 12 15 21
Mos
0
20
40
60
80
100
PFS(%)
18
Nivolumab + Ipilimumab in MSI-H Colon Cancer:
PFS per Investigators
Nivo 3 mg/kg
(n = 70)
Nivo 3 mg/kg
+
Ipi 1 mg/kg
(n = 30)
PFS rate, % (95% CI)
 6 mos
 9 mos
 12 mos
45.9 (29.8-
60.7)
45.9 (29.8-
60.7)
45.9 (29.8-
60.7)
66.6 (45.5-
81.1)
NE
NE
Median PFS, mos (95%
CI)
5.3 (1.5-NE) NE (3.4-NE)

P = .05 (t-test)
 TMB=229: POLE
(P286R; L1915I)
 TMB=176: POLE
(V411L)
P < .0001 (t-test)
Salem ME, et al. ASCO GI 2017. Abstract 530.
2 MSI-Stable CRCTumors With High TMB Carried POLE Mutations
1
10
100
500
400
300
200
80
60
50
40
30
20
7
5
4
3
2
0.7
MSI High MSI Stable
FA MSI
TMBperMB
10
30
20
7
5
4
3
6
MSI High MSI Stable
FA MSI
TMBperMB
9
8
Tumor Mutation Burden and MSI Are Highly
Correlated in GI Cancers

 Nivolumab Provides Durable Responses in
PatientsWith Metastatic DNA Mismatch
Repair–Deficient or MSI-High Colorectal
Cancer
 July 27, 2017
 This phase II study was designed to evaluate
response with nivolumab in patients with
MSI-high metastatic CRC.

 Of the 74 patients who were enrolled
between March 12, 2014, and March 16, 2016,
40 (54%) had received three or more
previous treatments.

 23 (31·1%, 95% CI 20·8-42·9) of 74 patients
achieved an investigator-assessed objective
response
 and 51 (69%, 57-79) patients had disease
control for 12 weeks or longer.

 Median duration of response was not yet
reached; all responders were alive,
 and eight had responses lasting 12 months or
longer

 Response to pembrolizumab in patients
with mismatch repair deficient (dMMR)
colorectal cancer (CRC).
 Citation:
J Clin Oncol 35, 2017 (suppl; abstr 3558)
 Nineteen pts were included in this analysis

 DCR at first assessment was 68%,
 with 5% CR,
 47% PR
 and 16% SD

 Median follow-up from diagnosis was 29 months
(95% CI 18-42).
 Median OS was 103 months (95% CI 85-103);
 12-month OS was 89%.
 Median OS from PD-1 therapy was 16.1 months
(95% CI 16-NR);
 12-month OS from PD-1 therapy was 79%.

 Median PFS was NR (95% CI 5-NR);
 12-month PFS was 54%.
 At time of analysis, 9 pts remain on PD-1
therapy;
 5 pts have died;
 3 have received subsequent therapy.

 THANKYOU FOR PATIENT LISTENING

Immunotherapy in metastatic colon cancer

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Immunotherapy in metastatic colon cancer

Similar to Immunotherapy in metastatic colon cancer (20)

Recently uploaded

Recently uploaded (20)

Immunotherapy in metastatic colon cancer