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IMMUNOTHERAPY STRATEGIES FOR COLORECTAL CANCER

Guillem Argilés, MD

Clinical Investigator, Gastrointestinal Malignancies

Programme

Early Drug Development Program

Vall d’Hebron University Hospital

Vall d'Hebron Institute of Oncology (VHIO)

◆ Understand the molecular basis of cancer immunotherapy

◆ To gain insight on the immunobiology and different therapeutic strategies for the

different immune subtypes of colorectal cancer

◆ MSI mCRC

◆ MSS mCRC

LEARNING OBJECTIVES OF

THE MODULE

◆ Introduction to cancer immunotherapy

◆ Overview of immunologic characteristics of CRC

◆ (Immunobiology of mCRC)

◆ Therapeutic immune strategies in CRC in MSI and MSS tumours

◆ Immune checkpoint inhibitors

◆ Adoptive cell therapies

◆ Anti-tumour vaccines

◆ Other agents

MODULE OUTLINE

INTRODUCTION TO CANCER IMMUNOTHERAPY

Immunotherapy is directed to the immune system compartment, not to the tumour

INTRODUCTION TO

IMMUNOTHERAPEUTICS

Tumour Progression Immune surveillance

As tumours progress

on their tumourigenic

cascades, the ability of

the immune system to

control tumour growth

decreases

Cancer immunotherapy

seeks to induce the

recovery of this ability

Adapted from Zitvogel L, et al. Nat Rev Immunol. 2006 Oct;6(10):715-27. Reprinted by permission from Springer Nature, Nat Rev Immunol, Cancer despite

immunosurveillance: immunoselection and immunosubversion, Zitvogel L, et al. Copyright 2006

Pre-malignant

lesion

ImmunosurveillanceElimination

Advanced

oncogenesis

ImmunoselectionEquilibrium

Tumour

growth

ImmunosubversionEscape

Cell intrinsic Cell extrinsic (immune system)

ANTI-TUMOUR IMMUNITY

Cell mediated

The anticancer response is cell mediated and either adaptive

(T-cell mediated) or innate (natural killer cell-dependent)

Cell mediated

Reprinted by permission from Springer Nature, Nature Reviews Cancer, Cytokines in cancer pathogenesis and cancer therapy, Dranoff G. Copyright 2004

Innate immunity

(rapid response)

Adaptive immunity

(slow response)

NATURAL KILLERS

Natural killers are responsible for detecting and killing virally infected

cells and cancer cells that do not express MHC class I

Failure of MHC class 1 to bind to the Killing Inhibitory Receptor (KIR) leads to tumour cell lysis

Reprinted by permission from Springer Nature, Nature Reviews Cancer, NK cells and cancer: you can teach innate cells new tricks, Morvan MG, et al.

Vol. 16; 7-19. Copyright 2016

1. Release of cancer

cell antigens

2. Cancer antigen

presentation

3. Priming and

activation

5. Infiltration of T cells

into tumours

6. Recognition of cancer

cells by T cells

7. Killing of cancer cells

4. Trafficking of T cells to tumours

MECHANISM OF ACQUIRED

CELL-MEDIATED IMMUNE RESPONSE

Reprinted from Immunity, 39(1), Chen DS, Mellman I, Oncology Meets Immunology: The Cancer-Immunity Cycle, 1-10, Copyright 2013, with permission from Elsevier.

TUMOUR ANTIGEN SHEDDING AND

PROCESSING ON APC

1. Tumour antigens of dying cells are released to

tumour microenvironment

2. Antigen Presenting Cells (APC) process these

antigens and present them through MHC class 2

3. Some populations of APC can cross-present the

phagocyted antigens through MCH class 1

DAMPs Immature DCDying

tumour cell

Reprinted by permission from Springer Nature, Nature Reviews Immunology, Cross-

presentation in viral immunity and self-tolerance, Heath WR, et al. Copyright 2001

Republished with permission of Annual Reviews, from Annu Rev Immunol,

Kroemer G, et al. 31:51-72, copyright 2013, permission conveyed through

Copyright Clearance Center, Inc.

ANTIGEN PRESENTATION BY APC

Once activated through antigen capturing and incorporation to the MHC, type 2 APCs migrate

to the loco-regional lymph nodes following chemokine gradients. Once in the lymph node, they

interact with the different populations of lymphocytes looking for T cell receptor compatibilities

Sanchez-Paulete AR, et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy, Ann Oncol. 2017;28(suppl_12):xii44-xii55,

by permission of The European Society for Medical Oncology (ESMO).

PRIMING IMMUNE SYNAPSE

Once the dendritic cells find a T helper cell or cytotoxic T cell with a compatible T cell receptor to the presented

antigen, both cells interact through three levels of signalling:

Signal 1: the so called MHC-TCR binding that depends on TCR specificity for the antigen

Signal 2: the interaction of the different activating and inhibitory immune checkpoint receptors and ligands

Signal 3: consisting of the exchanging of cytokines between both cells. The outcome of this signalling

determines whether there will be an immune response against the presented antigen or not

Pacheco R, et al (October 10th 2012). Cells, Molecules and Mechanisms Involved in the Neuro-Immune Interaction, Cell Interaction, Sivakumar Gowder, IntechOpen,

DOI: 10.5772/48367. Available from: https://www.intechopen.com/books/cell-interaction/cells-molecules-and-mechanisms-involved-in-the-neuro-immune-interaction.

Reproduced under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0).

Activation

Dead

PRIMING IMMUNE SYNAPSE

SIGNAL 2

Signal 2: The agonistic

and inhibitory ligands and

ligand receptors involved

are referred to as immune

checkpoints. Immune

checkpoint inhibitors

directed against PD-1/

PD-L1, CTLA-4, LAG-3,

ICOS, CD-40, OX-40

TIGIT constitute the main

current therapeutic field in

cancer immunotherapy

Reprinted by permission from Springer Nature, Nature Reviews Immunology, Molecular mechanisms of T cell co-stimulation and co-inhibition, Chen L, et al. Copyright 2013

LYMPHOCYTE TRAFFICKING

◆ Activated antigen reactive lymphocytes

abandon the lymph node and enter into the

circulation looking for zones of inflammatory

endothelium

◆ Inflammatory endothelium expresses

proteins that allow activated lymphocytes to

cross the endothelial barrier and enter into

the tissues

◆ The activated lymphocyte subsequently

moves towards the inflammatory focus

through a cytokine gradient that will direct

the lymphocyte to the inflammatory stimuli,

in this case the tumour

◆ This process may be hampered in case of

aberrant tumour vasculature

Gong C, et al. Front Immunol 2014;5:57. Reproduced under the terms of the Creative Commons Attribution License (CC BY 3.0; https://creativecommons.org/licenses/by/3.0/)

Reprinted by permission from Springer Nature, Nature Medicine, 19:1423-1437. Microenvironmental regulation of tumor progression and metastasis, Quail D, et al. Copyright 2013

TUMOUR MICROENVIRONMENT

Within the tumour microenvironment, activated lymphocytes usually have to cope with a myriad of

mechanisms, such as PD-L1 overexpression in tumour cells, paucity of nutrients, low tissue pH and T-helper

cell differentiation into regulatory T cells (Treg), which lead to a decreased anti-tumour immune response

IMMUNOLOGIC CHARACTERISTICS OF COLORECTAL CANCER (CRC)

With regard to treatment with immune checkpoint inhibitors, it is

important to discriminate between:

◆ Microsatellite Instable (MSI) CRC

◆ Microsatellite Stable (MSS) CRC

IMMUNOBIOLOGY OF CRC

◆ Microsatellites are repeats of 1 to 10 nucleotides with a variable

length (5–50 repeats), such as:

◆ A A A A A A A→ 7 poly-A microsatellite

◆ GT GT GT GT→ 4 poly-GT microsatellite

◆ ACGTCC-ACGTCC-ACGTCC→ 3 poly ACGTCC

◆ Microsatellites are localised in coding or non-coding DNA regions

MICROSATELLITES

Microsatellites cause DNA

polymerase slips in the replicative

fork causing DNA mismatches and

ultimately protein mutations

BIOLOGIC IMPORTANCE OF

MICROSATELLITES

◆ Zones of accumulations

of mutations

◆ Commonly frame shifts

Cox M, et al. Molecular Biology: Principles and Practice; 2nd Edition. WH Freeman and Company, New York

Evolution endowed eukaryotic cells with a dedicated system to repair mismatches in DNA

DNA MISMATCH REPAIR SYSTEM

Protein Heterodimer Repair function

MutSα MSH2 ♦ MSH6 Binds base-base

mismatches and insertion-

deletion mismatches

MutSβ MSH2 ♦ MSH3 Binds insertion-deletion

mismatches

MutLα MLH1 ♦ PMS2 Early step before excision

Vilar E, et al. Nat Rev Clin Oncol 2010;7(3):153-62;

Cox M, et al. Molecular Biology: Principles and Practice; 2nd Edition. WH Freeman and Company, New York

Human mismatch repair proteinsBinding of mismatch

proofreading proteins

DNA scanning detects nick in

new DNA strand (before

sealing by DNA ligase)

Repair DNA synthesisUp to 1000 bp can be removed

Strand removal

hMLH1

Error in newly

synthesized strand

hMSH2

◆ Alterations on microsatellite repairing system can be determined in two ways:

◆ By PCR against a group of microsatellites looking for mutations

◆ Given the name of microsatellite instable tumours

◆ By immunohistochemistry looking for the expression of the different mismatch

repair genes

◆ Given the name of mismatch repair deficient tumours

◆ The overlap between both techniques is 90%

◆ The frequency of MSI-H status in metastatic CRC is 5%

MSI-HIGH VS. MISMATCH REPAIR

DEFICIENT TUMOURS

THEORETICAL BASIS

For improved clinical benefit of treatment with checkpoint inhibitors in

case of microsatellite instability

◆ The loss of mismatch repair system causes mutations and ultimately cancer

◆ Colon cancers harbouring a defective mismatch repair system have a higher

number of neoantigens

◆ This increased mutational load increases the chance of a checkpoint inhibitor-

mediated anti-tumour response

TUMOUR RESPONSE TO ANTI-PD1

AXIS AGENTS ACCORDING TO

MICROSATELLITE STATUS

MSI CRC → Higher mutation tumour burden → higher lymphocyte infiltration → Responses to anti-PD-1 inhibitor

MSS CRC → LOW mutation tumour burden → low lymphocyte infiltration → No responses to anti-PD-1 inhibitor

Adapted from The Cancer Genome Atlas Network. Nature 2012;487:330–7. Reproduced under the terms of the Creative Commons Attribution-Non-Commercial-Share

Alike licence (http://creativecommons.org/licenses/by-nc-sa/3.0/).

From N Engl J Med, Le D, et al., Immune-therapy strategies for Colorectal Cancer, 372(26):2509–20. Copyright © 2015, Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.

OS in cohorts with CRC

WATERFALL PLOT OF MS-STABLE

AND -INSTABLE PATIENTS TREATED WITH

PEMBROLIZUMAB FOR MCRC

200 400 600

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100 MMR-proficient CRC

MMR-deficient CRC

MMR-deficient non-CRC

Days

%C

han

ge f

rom

Baseli

ne S

LD

MS-instable patients presented

dramatic responses in contrast

with MS-stable patients

MMR, mismatch repair

Le TD, et al. J Clin Oncol 2015;33(18 Suppl). Abstract LBA100. Presented at ASCO 2015. Courtesy of Dr Le.

Le TD, et al. N Engl J Med 2015;372(26):2509–20

CLINICAL TRIAL DESIGN:

KEYNOTE-164

A Phase 2, single-arm study of pembrolizumab in pretreated patients to

address significant patient unmet needs

Patient population

◆ Locally advanced or

metastatic MSI

CRC

◆ Patients must have

received at least

2 prior treatments

◆ Stage IV disease

Pembrolizumab 200 mg q3w IV

Complete

response

Discontinuation

permitted

Confirmed

progressive

disease

Discontinue

Partial response

or stable disease

Treat for up to 2 years

or until progression or

unacceptable toxicity

ORR by RECIST 1.1

Target enrollment: 60

Assessments: Radiological assessments using RECIST 1.1 and irRC every 9 weeks

Primary Endpoint

Le TD, et al. Ann Oncol 2018;29(suppl_5). abstract O-021 Presented at ESMO 20th World Congress on Gastrointestinal Cancer 20–23 June 2018,

Barcelona, Spain

MSI mCRC patients presented 32% RR regardless of the number of prior therapy lines

BEST PERCENTAGE CHANGE

FROM BASELINE IN TARGET

LESION SIZE*

*RECIST v1.1 per IRC. Data cutoff: September 12, 2017.

Le TD, et al. Ann Oncol 2018;29(suppl_5). abstract O-021 Presented at ESMO 20th World Congress on Gastrointestinal Cancer 20–23 June 2018, Barcelona,

Spain. Courtesy of Dr Le.

76% of patients alive at

1-year follow-up

OVERALL SURVIVAL

Data cutoff: September 12, 2017.

Le DT, et al. Ann Oncol 2018;29(suppl_5) abstract O-021. Presented at ESMO 20th World Congress on Gastrointestinal Cancer 20–23 June 2018, Barcelona,


PROGRESSION-FREE SURVIVAL*

*RECIST v1.1 per IRC. Data cutoff: September 12, 2017.

Le D, et al. Ann Oncol 2018;29(suppl_5) abstract O-021. Presented at ESMO 20th World Congress on Gastrointestinal Cancer 20–23 June 2018, Barcelona,


…and 41% progression-free

at 1-year follow-up

CHECKMATE 142

Nivolomab provided similar benefits (RR 31%, 48%

free from progressing and 74% alive 12 months

after treatment initiation)

Reprinted from Lancet Oncol, 18(9), Overman MJ, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal

cancer (CheckMate 142): an open-label, multicentre, phase 2 study :1182–91. Copyright 2017, with permission from Elsevier.

Patients, n

(%)

dMMR/MSI-H per Local

Laboratory (N=74)

dMMR/MSI-H per Central

Laboratory (n=53)

Investigator BICR Investigator BICR

ORR, n (%)

95% CI

23 (31.1)

20.8, 42.9

24 (32.4)

22.0, 44.3

19 (35.8)

23.1, 50.2

19 (35.8)

23.1, 50.2

Primary endpoint: ORR per investigator assessment

Secondary endpoint: ORR per blinded independent central review (BICR)

Other endpoints: PFS, OS, biomarkers, safety and tolerability

Histologically

confirmed metastatic/

recurrent CRC

dMMR/MSI-H per

local laboratory

≥1 prior line of

therapy

Nivolumab

3 mg/kg Q2W

Nivolumab

3 mg/kg Q2W

Patients Stage 1 Stage 2

Nivolumab

3 mg/kg +

ipilimumab

1 mg/kg Q3W

for 4 doses

Then

nivolumab

3 mg/kg Q2W

Stage 1

Nivolumab

3 mg/kg +

ipilimumab

1 mg/kg Q3W

for 4 doses

Then

nivolumab

3 mg/kg Q2W

Stage 2

Investigator PFS Investigator OS

Median (95% CI), months 9.6 (4.3, NR) NR (18.0, NE)

12-month rate (95% CI), % 50.4 (38.1, 61.4) 73.4 (61.5, 82.1)

Change in tumour burden

OVERALL SURVIVAL BY BEST

OVERALL RESPONSE

Very interestingly, none of the

responders died during the

trial follow-up, which

demonstrates the immunising

effect of the treatment

CR + PR

SD

PD

0 3 6 9 39

Months

Ove

rall

surv

ival

(%)

100

90

80

70

60

50

40

30

20

10

0

No. at Risk

CR + PR 25 25 25 25 25 25 19 14 14 13 9 5 1 0

SD 23 23 22 20 17 16 9 2 2 2 2 1 0 0

PD 22 15 12 10 9 7 4 1 1 1 1 0 0 0

NE = not estimable; NR = not reached.

Overman MJ, et al. J Clin Oncol 36, 2018 (suppl. 4S; abstr. 554). Presented at ASCO GI 2018. Courtesy of Dr Overman.

CR + PR

n=25

SD

n=23

PD

n=22

Median OS

(95% CI), months

NR

(NE)

NR

(14.3, NE)

10.3

(3.0, NE)

12 15 18 21 24 27 30 33 36

PEMBRO AND NIVO APPROVED IN

US BUT NOT IN EU FOR MSI MCRC

These ground-breaking results merited the

approval of pembrolizumab and nivolumab for

the MSI population in the refractory setting.

The EMA, however, halted the approval until

randomised data are analysed

Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm.

Accessed January 2019

Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm.

Accessed January 2019

Available at: https://www.ema.europa.eu/documents/withdrawal-letter/withdrawal-letter-

opdivo_en.pdf Accessed January 2019

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm

https://www.ema.europa.eu/documents/withdrawal-letter/withdrawal-letter-opdivo_en.pdf

◆ Grant the approval in Europe

◆ Move the treatment to earlier lines

◆ Maximise the percentage of responding patients

FUTURE GOALS OF

IMMUNOTHERAPY IN ADVANCED

MSI CRC

KEYNOTE 177 IS THE FIRST

RANDOMISED TRIAL EXPLORING

ANTI-PD1 AXIS BLOCKADE IN MSI-H MCRC

A Phase 3 study of pembrolizumab monotherapy vs. standard

chemotherapy in 1L MSI CRC

Keynote 177 will make it clear whether anti-PD1 inhibitors should become common frontline

practice in MSI mCRC and, if positive, could support final EMA approval for Europe

Patient population

◆ Locally advanced or

unresectable or

metastatic CRC

◆ MSIRandomisation 1:1

Pembrolizumab

200 mg q3w

Up to 2 years

PD

mFOLFOX6 + bevacizumab:

Bevacizumab 5 mg/kg

+

Oxaliplatin 85 mg/m2 IV

+

Leucovorin 400 mg/m2 IV

+

5-FU 400 mg/m2 IV bolus on

Day 1, then 1,200 mg/m2/day

for 2-day continuous infusion;

repeat every 2 weeks until

progressive disease

PD

PFS

OS

Target enrollment: 270

Primary Endpoint

Off study

Crossover

PD, disease progression

Diaz Jr LA, et al. J Clin Oncol 2016;34(Suppl 4S): Abstract TPS789

CHECKMATE 142: DOES CLINICAL

BENEFIT IMPROVE IF NIVOLUMAB

AND IPILUMUMAB ARE COMBINED?

Overman MJ, et al. J Clin Oncol 2018;36(8):773–9. Courtesy of Dr Overman.

3 512

26

31

38

51.3

31

3.4

0

20

40

60

80

100

Nivolumab + ipilimumabN=119

NivolumabN=74

Pat

ient

s (%

)

CR

PR

SD

PD

Unknown

ORR (95% CI):

31% (20.8, 42.9)ORR (95% CI):

55% (45.2, 63.8)

◆ DCR was 80% (95% CI: 71.5, 86.6) with combination therapy and 69% (57.1, 79.2)

with monotherapy

◆ Combination therapy provided a numerically higher ORR, including CRs, and DCR

relative to monotherapy during a similar follow-up period

INVESTIGATOR-ASSESSED

RESPONSE AND DISEASE CONTROL RATE

COMBINATION VS. SINGLE AGENT

71. Overman MJ, et al. Lancet Oncol 2017;18:1182–91; 2. Overman MJ, et al. J Clin Oncol 2018;36(8):773–9.

21

PROGRESSION-FREE AND

OVERALL SURVIVAL

COMBINATION VS. SINGLE AGENT

• With similar follow-up, combination therapy provided improved PFS and OS relative to monotherapya,e,f,2

11

Nivolumab +

ipilimumaba,dNivolumab1,e,f

9-month rate (95% CI), % 87 (80.0, 92.2) 78 (66.2, 85.7)

12-month rate (95% CI), % 85 (77.0, 90.2) 73 (61.5, 82.1)

Nivolumab +

ipilimumaba,bNivolumab1,e,f

9-month rate (95% CI), % 76 (67.0, 82.7) 54 (41.5, 64.5)

12-month rate (95% CI), % 71 (61.4, 78.7) 50 (38.1, 61.4)

aMedian follow-up 13.4 months (range, 9–25). bMedian PFS not reached (95% CI, not estimable). cPFS per investigator assessment. dMedian OS not reached (95% CI,

18.0, not estimable). eMedian follow-up 13.4 months (range, 10–32). fCheckMate-142 monotherapy and combination therapy cohorts not randomised or designed for a

formal comparison.

1. Overman MJ, et al. Lancet Oncol 2017;18:1182–1191; 2. Overman MJ, et al. J Clin Oncol 36(8), 2018: 773–9. Reprinted with permission. © 2018 American Society of

Clinical Oncology. All rights reserved. Courtesy of Dr Overman.

◆ Anti-PD-1 axis monoclonal antibodies produce dramatic and

long-lasting response in MSI CRC and are the new standard of care

in US

◆ Same will happen in the EU once randomised data are available

◆ Current efforts aim to move the treatment to earlier lines and

increase the % of patients who respond to treatment

◆ Anti-CTLA4 + anti-PD-1 agents will soon become new standard

of care

CONCLUSIONS

MSS CRC

◆ Immune checkpoint inhibitors and specifically-designed

immunotherapy combinations failed to improve outcome

BACKGROUND

Pembrolizumab1 Nivolumab + Ipilimumab2 Cobimetinib + Atezolizumab3

Nivolumab

1 mg/kg +

ipilimumab

3 mg/kg

(n=10)

Nivolumab

3 mg/kg +

ipilimumab

1 mg/kg

(n=10)

ORR, n (%) 1 (10) 0

Median PFS,

mo (95% CI)

2.28

(0.62, 4.40)

1.31

(0.89, 1.71)

Median OS,

mo (95% CI)

11.53

(0.62, NE)

3.73

(1.22, 5.62)

1. From N Engl J Med, Le D, et al., Immune-therapy strategies for Colorectal Cancer, 372(26):2509–20. Copyright © (notice year) Massachusetts Medical Society. Reprinted

with permission from Massachusetts Medical Society;

2. Overman MJ, et al. J Clin Oncol 34, 2016 (suppl; abstr 3501. Presented a ASCO 2016;

3. Bendell J, et al. Ann Oncol 2018;29(suppl_5) ESMO WGI 2018; abstract LBA-004. Courtesy of Dr Bendell.

Time (months)

Ove

rall

surv

ival

(%

)

100

80

60

40

20

0

0 3 6 129 15 18 21

Atezolizumab + cobimetinib

Atezolizumab

Regorafenib

Tumour mutational burden and ORR correlation with anti–PD-1 axis

agents in 27 tumour types1

CONSIDERING THE MUTATIONAL

BURDEN OF MSS CRC RESPONSE RATE TO

TREATMENT WITH ANTI-PD-1 AXIS AGENTS IS LOW

1. From N Engl J Med, Yarchoan M, et al. Tumor Mutational Burden and Response Rate to PD-1 Inhibition., 377(25 ):2500-2501. Copyright © 2017. Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

2. Reprinted from Cancer Discovery, 2018; 8(6):730–49, Grasso CS, et al., Genetic Mechanisms of Immune Evasion in Colorectal Cancer, with permission from AACR.

THIS COULD BE EXPLAINED BY ITS

IMMUNOSUPPRESSIVE BIOLOGY, WHICH IS

CAUSED BY GENOMIC ALTERATIONS

The described stepwise model of CRC carcinogenesis starts with WNT path activation

1. The Cancer Genome Atlas Network, Nature 2012490, pages 61–

70; under the terms of the Creative Commons Attribution-Non-

Commercial-Share Alike licence

(http://creativecommons.org/licenses/by-nc-sa/3.0/),

2. Reprinted by permission from Springer Nature, Nat Rev Cancer,

Walther A, et al. Genetic prognostic and predictive markers in

colorectal cancer. Copyright 2009

3. Fearon ER, et al. Cell 1990;61(5):759–67

WNT PATHWAY ACTIVATION LEADS

TO DENDRITIC CELL EXCLUSION FROM

TUMOUR MICROENVIRONMENT Melanoma1 Localised CRC2 mCRC3

1. Reprinted by permission from Springer Nature, Nature, Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity, Spranger S, et al. Copyright 2015;

2. Reprinted from Cancer Discovery, 2018; 8(6):730–49, Grasso CS, et al., Genetic Mechanisms of Immune Evasion in Colorectal Cancer, with permission from AACR;

3. Rodón J, et al. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer

Res 2018;78(13 Suppl):Abstract nr CT175.

MSS mCRC HAS AN

IMMUNOSUPPRESSANT BIOLOGY

The second step is the activation of the MAPK-PI3K pathway









MAPK-PI3K PATHWAY ACTIVATION

IMPAIRS ANTIGEN PRESENTATION BY

DECREASING MHC CLASS 1 EXPRESSIONCD8+ T cells

per tumour cell

Proportion of IFNγ-producing

CD8+ T cells

60

0

20

40

80

MEKiNo drug

IFN

γ+(%

)

Proportion of CD8+ cells

with low PD-1 expression

40

30

0

10

20

50

MEKiNo drugP

D-1

lo/C

D8+

cel

ls (

%)

0.04

0.03

0

0.01

0.02

MEKiNo drug

MHC class 1

1. Reprinted from Immunity, 44(3), Ebert PJR, et al. MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade, 609–21;

Copyright 2016, with permission from Elsevier; 2. Bendell J, et al. J Clin Oncol, 34(15_suppl) 2016: 3502. Presented at ASCO 2016. Permission granted by author, Dr Bendell.

MSS mCRC HAS AN


The third step is the intracellular loss of function of the TGF-beta pathway









TGFβ blockade in combination with PD-1 axis inhibition can

reverse this process and induce anti-tumour immune responses

TGFβ ACTIVATION

TGFβ activation in the tumour microenvironment is a primary mechanism of

immune evasion that promotes T-cell exclusion and blocks acquisition of the

TH1-effector phenotype

Bladder Cancer

CRC

1. Reprinted by permission from Springer Nature: Nature, TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis,Tauriello DVF, et al. Copyright 2018;

2. Reprinted by permission from Springer Nature: Nature, TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells, Mariathasan S, et al. Copyright 2018

MSS mCRC HAS AN


The fourth step is the P53 pathway inactivation









• Wild type p53 in tumours unleashes the

CTL response via inhibition of PD-L1 and

enhances their effectiveness by

upregulating Fas/APO-1 and MHC I

• Given that p53 is mutated in

approximately 50% of human cancers and

also impacts the immunoreactivity of

cancer cells, a significant number of

patients can be affected by the impaired

CTL response that results from non-

functional p53

• An attenuated CTL response due to p53

mutations could decrease response rates

to immunotherapeutic drugs, leading to

poor patient prognoses

TP-53 PATHWAY INACTIVATION

CONTRIBUTE TO IMMUNE ESCAPE

Braun MW, et al. Transl Cancer Res. 2016 Dec; 5(6): 692–697; Translational cancer research by NANCY INTERNATIONAL LTD SUBSIDIARY AME

PUBLISHING COMPANY. Reproduced with permission of NANCY INTERNATIONAL LTD SUBSIDIARY AME PUBLISHING COMPANY in the format Use in an

e-coursepack via Copyright Clearance Center.

THE COMPLEXITY OF

IMMUNOTHERAPEUTICS

Contrary to normal cancer therapeutics, cancer immunotherapy is based on a bi-compartment

model where tumour and immune system interact constantly

Biologic compartments implied

in normal cancer therapeutics

Biologic compartments implied

in immunotherapeutics1

One-compartment model Two-compartment model

1. Adapted from Immunity, 39(1), Chen DS & Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle, 1-10, Copyright 2013, with permission from Elsevier.

https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi7q9TgtfHcAhUBjqQKHdmvA1gQjRx6BAgBEAU&url=https://www.cell.com/immunity/abstract/S1074-7613(13)00296-3&psig=AOvVaw2zrIs6H9-g6Ld_oD0r2JTb&ust=1534503664018928

TRANSCRIPTOMIC

CLASSIFICATION OF CRC

• Gene signatures can capture the bi-compartmentation of cancer immunotherapy

• The most validated gene-signature for mCRC is the Consensus Molecular Subtype

Classifier that divides CRC in four molecular subtypes.

Guinney J, et al. Nat Med 2015;21(11):1350–6

CMS1

MSI Immune

CMS2

Canonical

CMS3

Metabolic

CMS4

Mesenchymal

14% 37% 13% 23%

MSI, CIMP high

HypermutationSCNA high

Mixed MSI status

SCNA low, CIMP lowSCN high

BRAF mutations KRAS mutations

Immune infiltration

and activation

WNT and MYC

activationMetabolic deregulation

Stromal infiltration

TGF beta activation

Angiogenesis

Worse survival

after relapse

Better survival

after relapse

Worse relapse-free

and overall survival

TRANSCRIPTOMIC

CLASSIFICATION OF CRC

CMS1 behaves like

MSI tumours at an

RNA level

CMS2 depends on

WNT activation

CMS3 harbours MAPK

pathway activation and

metabolic reprogramming

CMS4 is characterised by

stromal TGFβ activation

and diffuse inflammation

Guinney J, et al. Nat Med 2015;21(11):1350–6

CMS1

MSI Immune

CMS2

Canonical

CMS3

Metabolic

CMS4

Mesenchymal

14% 37% 13% 23%

MSI, CIMP high

HypermutationSCNA high

Mixed MSI status

SCNA low, CIMP lowSCN high

BRAF mutations KRAS mutations

Immune infiltration

and activation

WNT and MYC

activationMetabolic deregulation

Stromal infiltration

TGFβ activation

Angiogenesis

Worse survival

after relapse

Better survival

after relapse

Worse relapse-free

and overall survival

IMMUNE LANDSCAPE OF MSS

mCRC ACCORDING TO CMS SUBTYPE

MSI-LIKE WNT pathway activation MAPK / PI3Kactivation

TGFβ

CMS1 behave like MSI tumours. CMS2 and CMS3 are cold tumours, while

CMS4 harbour a non-anti-tumoral inflammatory microenvironment

Adapted from Clinical Cancer Research, © 2016, 22(16), 4057–66, Becht E, et al. Immune and Stromal Classification of Colorectal Cancer Is Associated with

Molecular Subtypes and Relevant for Precision Immunotherapy, with permission from AACR.

T cells chemotaxis

and activation

T-cell-specific inhibitionMyeloid-cells chemotactism

Angiogenesis

Immunosuppression

Complement

Tertiary lymphoid structures

Major Histocompatibility Complex I

(MHCI)

CMS1: MSI-LIKE SUBGROUP WITH

HEALTHY TILS

Strategy:

PD1 blockade

Immune

CMS1

MSI

PD1 blockade

responsive

FDA approval:

Nivolumab

Pembrolizumab5%

10%

Anti-PD-1 therapies could achieve the same results in CMS1, as seen in MSI tumours.

Motricolor CT3 trial (atezolizumab + bevacizumab) is exploring this hypothesis



CMS1

T cells chemotaxis

and activation

T-cell-specific inhibition

Myeloid-cells chemotactism

Angiogenesis

Immunosuppression

Complement


MHCI

CMS2 WNT ACTIVATION

Block Wnt pathway

Allow dendritic cell infiltration

Foster T-cell anti-tumour

reactivity

NCT02675946 (Wnt pathway inhibition):

CGX1321 Porcupine inh + Pembrolizumab

for mCRC

CMS2 is characterised by Wnt pathway activation and by having a cold tumour microenvironment.

WNT inhibition may foster anti-tumoral immune response in these tumours

CMS2

Wnt pathway activation

T cells chemotaxis

and activation



Angiogenesis

Immunosuppression

Complement


MHCI



Wnt pathway inhibitors are, however, often not effective due to downstream APC

mutations

◆ LRP 5/6 Inh

◆ Anti-RSPONDIN MoAb

◆ Porcupine inhibitor

WNT PATHWAY INHIBITORS

Clevers & Nusse. Cell 149, June 8, 2012Mc Donald Clevers & Nusse. Cell 149, June 8, 20121. Reprinted from Developmental Cell, 17, MacDonald BT, et al. Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases, 9–26; Copyright 2009, with permission

from Elsevier; 2. Reprinted from Cell, 149(6), Clevers H, et al. Wnt/β-Catenin Signaling and Disease 192–205, Copyright 2012, with permission from Elsevier.

Seshagiri S, Nature 2012; Koo BK, Nature 2012

Giannakis M, Nat Genetics 2014

CMS3: DEPENDS ON MAPK

PATHWAY ACTIVATION

MAPK/PI3K

activation1

Rational approach should be MEK + PD-1 axis inhibition2

1. Adapted from Clinical Cancer Research, ©2016, 22(16), 4057–66, Becht E, et al. Immune and Stromal Classification of Colorectal Cancer Is Associated with

Molecular Subtypes and Relevant for Precision Immunotherapy, with permission from AACR;

2. Bendell J, ESMO-WGI 2018. Courtesy of Dr Bendell.

CMS3

Unresectable

mCRC patients

Received at least

2 regimens in

metastatic setting

(not including

maintenance)

2:1:1

N=360

ARM ACobimetinib + atezolizumab

n=180

ARM BAtezolizumab

n=90

ARM CRegorafenib

n=90

Treatment to

continue until

loss of clinical

benefit

COTEZO TRIAL

OVERALL SURVIVAL

Atezo + cobi(n=183)

Atezo(n=90)

Rego(n=90)

Median OS, mo(95% CI)

8.9 (7.00, 10.61)

7.1 (6.05, 10.05)

8.5 (6.41, 10.71)

HR vs. rego(95% CI)

1.00 (0.73, 1.38)

1.19 (0.83, 1.71)

N/A

P-value 0.9871 0.3360a N/A

12-mo OS, % 38.5 27.2 36.6

The MEK inh./ PD-L1 inh-combination did not achieve a better outcome

The COTEZO trial was

negative for the overall

population.

Outcomes of the CMS3

population need to be

determined to validate the

hypothesis

Bendell J, et al. Ann Oncol 2018;29 Suppl 5:v123, abstract LBA-004. Presented at ESMO WGI 2018. Courtesy of Dr Bendell.

Future directions for CMS 3

NCT02876224: Cobimetinib + atezolizumab + bevacizumab for 2nd line MSS mCRC

NCT02060188: Cobimetinib + Ipilimumab + Nivolumab for MSS mCRC

NCT03271047: Binimetinib + Nivolumab +/- Ipilimumab for RAS mut mCRC

CMS3 MAPK PATHWAY ACTIVATION

1. Adapted from Clinical Cancer Research, © 2016, 22(16), 4057–66, Becht E, et al. Immune and Stromal Classification of Colorectal Cancer Is Associated with

Molecular Subtypes and Relevant for Precision Immunotherapy, with permission from AACR; 2. Segal N, et al. J Clin Oncol 36, 2018 (suppl; abstr 3540).

Presented at ASCO 2018. Courtesy of Dr Segal.

MAPK/PI3K

activation1

CMS3

Natural killer cell therapy

Monalizumab

+

Durvalumab

MSS mCRC 3/39 PRs

Natural Killers are the cells

that kill those cells that do

not express MHC class 1

Change in Tumor Size in MSS-CRC Patients in the Expansion Phase2

CMS4: TGFβ ACTIVATION

NCT03436563: M7824 (bi-specific TGFβ/PD-L1 MoAb) for CMS 4 mCRC2

Block TGFβ pathway in CMS 4 mCRC

Change the inflammatory microenvironment

to a Th1 immune response

Foster T-cell infiltration

Increased sensitivity to

Immune checkpoint inhibitors

1. Adapted from Clinical Cancer Research, © 2016, 22(16), 4057–66, Becht E, et al. Immune and Stromal Classification of Colorectal Cancer Is Associated with

Molecular Subtypes and Relevant for Precision Immunotherapy, with permission from AACR;

2. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03436563. Accessed January 2019

CMS4

TGFβ1

CRC IMMUNE CLASSIFICATION AT

TRANSCRIPTOMIC LEVEL

Hypermutation WNT Pathway activation KRAS m TGFβ

TREATMENTS FOR ALL SUBGROUPS



T cells chemotaxis

and activation



Angiogenesis

Immunosuppression

Complement


MHCI

CHEMOTHERAPY OR

RADIOTHERAPY–IMMUNE CHECKPOINT

INHIBITOR COMBINATIONS Target Therapy Phase Trial Design Trial ID

Anti-PDL1

Atezolizumab (engineered IgG1,

no ADCC)

I Solid tumours NCT01375842

Ib Solid tumours (+ bevacizumab ± FOLFOX) NCT01633970

II mCRC (+ bevacizumab + fluoropyrimidine) NCT02291289

MEDI4736(modified IgG1,

no ADCC)II mCRC NCT02227667

Anti-PD-1

Nivolumab(IgG4)

I/II mCRC (± ipilimumab) (CheckMate 142) NCT02060188

I/II Solid tumours (+ INCB24360) NCT02327078

I/II Solid tumours (+ chemotherapy) NCT02423954

I/II Solid tumours (+ varlilumab) NCT02335918

Pembrolizumab(IgG4, humanised)

I Solid tumours (+ aflibercept) NCT02298959

I/II GI cancers (+mFOLFOX6) NCT02268825

I/II WT mCRC (+ cetuximab) NCT02318901

II mCRC (+ radiotherapy or ablation) NCT02437071

II mCRC (+ chemotherapy) NCT02375672

II mCRC (+ azacitidine and/or romidepsin) NCT02512172

II MSI-positive/-negative CRC NCT01876511

*Recruiting studies

Clinicaltrials-gov

◆ Binds simultaneously with one arm to CD3 on T cells and with two arms to CEA on tumour cells

◆ Flexible 2-to-1 format enables high-avidity binding and selective killing of CEA-overexpressing tumour cells

◆ Longer half-life compared with other TCB formats

◆ Silent Fc results in reduced risk of FcγR-related cytokine release/IRRs

CEA-TCB structure1,2

BI-SPECIFIC T-CELL

ENGAGING ANTIBODIES

Direct T-cell activation skipping antigen

recognition upon binding to CEA protein

◆ Simultaneous binding of TCB to tumour (CEA) and T cells (CD3)

◆ Killing of tumour cells independent of pre-existing immunity

◆ T-cell proliferation at site of activation

Fab, fragment antigen-binding region; IRR, infusion-related reaction.

Adapted from: 1. Bacac M, et al. Clin Cancer Res. 2016; and 2. Bacac M, et al. OncoImmunology. 2016;

Argilés G, et al. CEA-TCB in CRC. ESMO WGI 2017. Courtesy of Dr Argilés.

Source: Juno official website

Study 2: CEA-TCB + atezolizumab (n=11, 80 and 160 mg of CEA-TCB)

p

*p

*

p

-50

0

50

100*p

WithdrawalProgressionOngoingFirst new lesion

a

160 mg80 mg

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

CEA-TCB AT DOSES ≥60 MG +

ATEZOLIZUMAB IN 3L+ PATIENTS

WITH MSS MCRC

Bes

t ch

ang

e in

tar

get

lesi

on

s

fro

m b

asel

ine,

%

Weeks after treatment start

*p

Withdrawal

Progression

Ongoing

First new lesion

160 mg

80 mg

Data reported by investigators, cut-off: March 3, 2017. aRadiological signs of tumour inflammation seen at ≥ 60 mg (safety data cut-off is ≥ 40 mg).

Argilés G, et al. Ann Oncol 2017;28(suppl_3); abstract LBA-004. Presented at ESMO WGI 2017. Courtesy of Dr Argilés.

A PHASE I STUDY OF

ENADENOTUCIREV

An oncolytic Ad11/Ad3 chimeric group B adenovirus, in combination with

nivolumab in tumours of epithelial origin

Harb W, et al. J Clin Oncol 35, 2017 (suppl; abstr TPS3115). Presented at ASCO 2017. By permission from PsiOxus and courtesy of Dr Harb...

A PHASE I STUDY OF

ENADENOTUCIREV

An oncolytic Ad11/Ad3 chimeric group B adenovirus, in combination with

nivolumab in tumours of epithelial origin

Harb W, et al. J Clin Oncol 35, 2017 (suppl; abstr TPS3115). Presented at ASCO 2017. By permission from PsiOxus and courtesy of Dr Harb..

Personalised immune therapies are a good option in expert hands

PERSONALISED IMMUNE

THERAPIES

Personalised peptide vaccines1 Adoptive T-cell therapy2

1. Reprinted from Clin Cancer Res, 2016, 22(4):807-12, Desrichard A, et al., Cancer Neoantigens and Applications for Immunotherapy, with permission from

AACR; 2. Reprinted by permission from Springer Nature, Nature Reviews Cancer, Adoptive cell transfer: a clinical path to effective cancer immunotherapy,

Rosenberg SA, et al. Copyright 2008.

◆ Personalised immune therapies can be good options for patients not

responding to other available therapies

◆ However, their complexity makes these options only available in

highly experienced centres, since their success depends on the

experience of the team

PERSONALISED IMMUNE

THERAPIES

EXAMPLES OF VACCINES FOR

IMMUNOSTIMULATION IN CRC

Therapy Antigen Enhancer Phase Study population Trial ID

Anti-tumour

vaccines

Autologous

tumour cells

BCG

II Adjuvant CRC PMID: 8445413

III Adjuvant CRC PMID: 15755632

III Adjuvant Stage II CRC NCT02448173

Newcastle

Disease Virus II Liver ressected CRC PMID: 18488223

Dendritic cell

vaccines

CEA Dendritic cells I Adjuvant Stage III CRC NCT01890213

MUC 1 Dendritic cells IILiver or lung ressected

CRCNCT00103142

Pubmed - Clinicaltrials.gov

Clinicaltrials.gov

EXAMPLES OF ADOPTIVE CELL

THERAPY FOR IMMUNOSTIMULATION

IN CRC

Therapy Target Enhancer Phase Trial Design Trial ID

TILSAutologous

tumour cells

IL-2

PembrolizumabII GI tumours NCT01174121

CAR T cells

CEA ITumours expressing

CEANCT02349724

CEA Yttirum 90 ITumours expressing

CEANCT02416466

EGFR I/IITumours expressing

EGFRNCT01869166

Cytokine-

induced-

killers cells

Autologous

tumour cellsII

Adjuvant CRC in

combination with

XELOX

NCT01929499

◆ Immune checkpoint inhibitors and MEK-based combinations have

failed in MSS mCRC, potentially reflecting the lack of implementation

of tumour biology knowledge into study design

◆ A new generation of promising compounds and combinations

specifically designed for this disease are currently entering clinical

development

◆ Deeper understanding of tumour biology is crucial to ensure their

success and further implementation in clinical practice

TAKE HOME MESSAGES FOR

MSS MCRC

THANK YOU!

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