state of the art in development of immunotherapy alex a. adjei€¦ · ©2016 mfmer | slide-3. two...

©2016 MFMER | slide-1

State of the Art in Development of Immunotherapy

Alex A. AdjeiESMO AFRICACape TownFebruary 15, 2018


DISCLOSURE OF INTEREST

Alex A. Adjei

Institutional financial interests :

Clinical trial Funding : MSD, Piqur, Macrogenics, Kura


Two Types of Immune Responses ProvideExtended Protection

1. Murphy K. Janeway’s Immunobiology. 8th ed. New York, NY: Garland Science; 2012.2.Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; 2012.

CANCEROUS CELLS

PhysicalBarriers

InnateImmunity

AdaptiveImmunity

3


Innate Immune Cells

MacrophagesGranulocytes Monocyttees

Macrophage B cell Dendritic cell

Cytotoxic T cell

TregsHelperT cell

Engulf microorganisms or kill them by releasingtoxic molecules

Reside in almost alltissues, destroy microorganisms and deadcells and help recruitmentof other immune cells

Ingest foreignparticles, are theprecursors of macrophages

Found in lymphoidand non-lymphoidtissue, activatenaïve T cells, help trigger adaptive immune response

Tumor cell

CD8+ cells,also calledcytotoxic T lymphocytes(CTL), kill virus-infectedcells and tumor cells

CD4+ cellsproduce cytokinesthat help activatevarious cells and support B-cellantibodyproduction

Regulatory Tcells (Tregs)suppress theactivity of manycell types andhelp controlimmune responses

APCs

Immune Effector Cells


Proper T-Cell Activation Requires 2 Signals• To be properly activated, a T cell MUST receive 2 signals

– Binding of an MHC-antigen complex to TCR

– Binding of a second costimulatory signal

• This initiates intracellular signaling that activates the T cell, which can then kill infected or cancer cells or help support other immune functions

CostimulationT cell

1. Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; 2012.2. Mellman I et al. Nature. 2011;480(7378):480–489.

Antigen

MHC

APC:Tumor

cellEffector functions

APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor.

Image © 2012 from Janeway’s Immunobiology, Eighth Edition by Murphy. Adapted by permission of Garland Science/Taylor & Francis LLC.


Targeting Immune Mechanisms in the TumorMicroenvironment

TIL = tumor-infiltrating lymphocytes

Immune Checkpoint Inhibition and Costimulatory Molecule Agonism3,4

Therapeutic targeting of immune

checkpoints is designed to reverse tumoral suppression of T-cell activity, while agonism of

costimulatory molecules aims to enhance tumor-specific

T-cell activation

Adoptive T-cell Transfer2

Increases the frequency of tumor-antigen-specific T cells by growing T cells harvested from a tumor sample in vitro

and then reinfusing themTumor-

infiltrating T cells

Therapeutic Vaccines2

Designed to generate a specific active

immune response against tumor

antigens

Cytokines1

Stimulates a nonspecific immune

response by boosting the activity of immune

effector cells and stromal cells at the

tumor siteStromal cell

40

Effectorcell

1. Lee S, Margolin K. Cancers (Basel). 2011;3(4):3856-3893. 3. Mellman I et al. Nature. 2011;480(7378):480-4892. Spranger S et al. J Immunother Cancer. 2013;1:16. 4. Schaer DA et al. J Immunother Cancer. 2014;2:7.


Cosignaling Molecules Contribute to Immune Regulation• Cosignaling regulates

T-cell activation– Signaling via costimulatory molecules (eg,

CD28, GITR) promotes T-cell activation– Signaling via coinhibitory molecules (eg,

PD-1, LAG-3), also termed “immunecheckpoints,” suppresses T-cellactivation

• APCs can express thesignaling partners of thesecostimulatory and coinhibitory molecules anddirect T-cell accordingly

Costimulatory molecules

8

Coinhibitory molecules

1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.2. Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; 2012.3. Mellman I et al. Nature. 2011;480(7378):480–489.


Lesson 1The Checkpoint Inhibitors really work !!!


Baseline Post C2 (Week 6) Post C4 (Week 12)

64-year-old male with squamous NSCLC s/p R lobectomy, progressed on cisplatin + gemcitabine, docetaxel, erlotinib. Treated with Atezolizumab (1200mg iv q 3wks)


Immune checkpoint inhibitors have demonstrated responses across several tumour types

100

0

–100

*

–50

50

Confirmed complete response (nodal disease)Confirmed partial responseStable diseaseProgressive disease

Breast cancer treated with pembrolizumab1 NSCLC treated with durvalumab2

PD-L1+ PD-L1-C

hang

e fr

om b

asel

ine

in s

um o

f lo

nges

t dia

met

er o

f tar

get l

esio

n, %

100

0

–100

–50

50

Best

cha

nge

from

bas

elin

e (%

)

ORR 19%PD 44%

ORR 27%PD NA

ORR 5%PD NA

Max

imum

SLD

redu

ctio

n fr

om b

asel

ine

(%)

100

0

–100

*

Complete responsePartial responseProgressive diseaseStable disease

UC IC2/3 treated with atezolizumab3

ORR 27% PD 43%

Spectrum of Activity of Immune Checkpoint Inhibitors• Long lasting responses in

patients with:• Melanoma (30-35%)• NSCLC (20-25%)• Bladder (25%)• Hodgkin’s (65-85%)• Merkel cell carcinoma (71%)• Head and neck• Gastric• Ovarian• Colorectal• Liver• Mesothelioma• SCLC• MSI high/MMR tumors

PD-1/PD-L1 Blockad

e

Mel RCCNSCLC

Bladder

HNSCC

HodgkinB-

cell NHL

MSI-high CRC

Ovarian

TNBC

Mesothe

-liom

a

HCC

Esopha-geal

GBM


U.S. FDA Approved PD1/PDL1 Axis Inhibitors Melanoma Pembrolizumab, Nivolumab, Nivolumab + IpilimumabNon-Small Cell Lung Ca

Nivolumab, Pembrolizumab, Atezolizumab, Pembrolizumab + Carboplatin/ Pemetrexed

Renal Cell Ca Nivolumab, PembrolizumabUrothelial Ca Atezolizumab, Pembrolizumab, Avelumab,

Durvalumab, NivolumabHodgkins Lymphoma Nivolumab, PembrolizumabHead & Neck Ca Pembrolizumab, NivolumabMerkel Cell Ca AvelumabMSI-high/ dMMR Ca Pembrolizumab, Nivolumab (if Colon Ca)Gastric CA PembrolizumabHepatocellular CA Nivolumab


Lesson 2

There are durable responses – Could some patients with metastatic disease be cured ?


Female (66 y.o) with squamous cell lung cancer s/p 3 chemotherapy regimenss. Referred to our phase I clinic. Received nivolumab in 2011

January 2011 December 2016


Long term survival in patients with heavily pretreated metastatic NSCLC

CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

Median OS (95% CI), mo

Overall (N = 129) 9.9 (7.8, 12.4)

100

80

60

40

20

00 1 2 3 4 5 6 7 8

129 49 27 20 17 16 3 1 0

YearsNo. at Risk

OS

(%)

1 y OS, 42%

2 y OS, 24%3 y OS, 18% 5 y OS, 16%

aThere were 3 deaths between 3 and 5 years, all due to disease progression; 1 surviving patient was censored for OS prior to 5 years (OS: 58.2+ months)

Brahmer J, AACR 2017


Lesson 3

• How long should we treat ?

19


Exploratory Analysis• Improvement in PFS (HR 0.42), 1 year

PFS: 65% vs 40%• Improvement in PFS independent from

RR• Trend in OS (HR 0.63)• Some stabilizations by reexposure

A Signal – CheckMate 153

Spigel D et al, ESMO 2017; abstract 1297O


Lessons learned 4

Response to treatment can be atypical : Pseudoprogression

©2016 MFMER | slide-22Case courtesy of Caroline Robert, Gustave Roussy, Villejuif

Pseudoprogression with pembrolizumab –response after initial progression


Ipilimumab Responses After the Appearance and Subsequent Disappearance of New Lesions

3 mg/kg Ipilimumab q3wks X 4

Pre-Treatment

Wk 36: Still Regressing

Wk 12: Progression

Wk 20: Regression

New lesions

Wolchok et al, 2008a.

July 2006


Pseudo-progression may reflect development of antitumor immunity

• Antitumor immune response can appear as disease progression (tumor growth or appearance of new lesions)—known as pseudo-progression1

• Pseudo-progression may be misclassified as disease progressionBASELINE ASSESSMENT FIRST ASSESSMENT LATER ASSESSMENT

NK cellT cell

Pseudo-progression

Disease progression

Although uncommon, pseudo-progression should be considered until disease progression can be confirmed

Lesson #5 : Unusual Toxicities Occur: Immune related Adverse Events (IRAEs)

MSKArthralgia,

myalgia, arthritis, myosititis

GeneralFatigue,

asthenia, fever, chills, infusion related reaction

Inflammatory processes affecting any organ system

Distinct mechanism of action from traditional chemotherapy-related side effects

Evaluation and management are unique to this class of drugs

May be exacerbated by underlying autoimmune conditions/presence of autoantibodies


Case

• 72 y/o with metastatic squamous cell lung cancer

• Docetaxel/carboplatin x 4 cycles

• Gemcitabine/carboplatin x 4 cycles

• Nivolumab x 8 cycles with PR but new infiltrates

• Bronchoscopy with BAL and biopsy


AFB, PCR +ve for M. tuberculosis

Diffuse lymphocytic infiltration were in the alveolae

Fujita et al, JTO 2016.


Can we Identify patients who will benefitfrom immunotherapy ?

28


What is the Ideal Biomarker ?

• Validated• Quantifiable or binary • Sensitive and specific. • Simple and adaptable to clinical use,

with a quick turnaround time• Present in easily accessible tissues


We know that PD-L1 expression has clinical relevancePD-L1+ cancers demonstrate higher response rates in a wide variety of cancers regardless of the PD-L1 assay or the PD-1/PD-L1 agent used

Adapted from Callahan: ASCO 2014


Tumor Mutational Burden (TMB)


High TMB is associated with response to checkpoint inhibition

DCB: Durable clinical benefit (PR/SD >6months)NDB: No durable benefit

Rizvi. Science 2015


What mutations to “count” in TMB

SNVs

Synonymous

Non-synonymous

Rizvi. WCLC 2017


Tumor Mutational BurdenCheckMate 026 TMB Analysis: Nivolumab

in First-line NSCLC

Whole exome sequencinga

Tumor DNA

GermlineDNA (blood)

Somatic missense mutations

Tumor exome

data

Germline exome

data

TMB

aDNA was sequenced on the Illumina HiSeq 2500 using 2 × 100-bp paired-end reads; an average of 84 and 89 million reads were sequenced per tumor and germline sample, respectively (average 84.6 × and 93 × the mean target coverage, respectively)

Peters, S et al. AACR 2017

TMB tertile

Total missense mutations, no.

Low 0 to <100

Medium 100 to 242High ≥243

TMB - Definition


S. Peters et al, AACR 2017


Cellular infiltrates within the Tumour microenvironment

Kerkar & Restifo. Cancer Res 2012


Inhibiting PD-1-mediated adaptive immune resistance

Melanoma cellor tumor macrophage

Interferons

Anti-PD-1Anti-PD-L1

Taube et al. Sci Transl Med 2012Tumeh et al. Nature 2014


Inhibiting PD-1-mediated adaptive immune resistance

Melanoma cellor tumor macrophage

Interferons

Anti-PD-1Anti-PD-L1

Tumeh et al. Nature 2014


Evolution of CD8+ T-cells, According to Treatment Outcome

IHC Analysis of CD8+ T-cells in samples obtained before and during anti-PD1 treatment

Paul C. Tumeh, Christina L. Harview, I. Peter Shintaku, Emma J. M. Taylor


Management of cancer in the post-anti-PD-1/L1 era

Anti-PD-1/anti-PD-L1

Generate T cells:

+ anti-CTLA4+ immune activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ targeted therapies

Bring T cells into tumors:

VaccinesTCR engineered ACTCAR engineered ACT


Planned and ongoing trials


Pertinent issues withImmunotherapy in Africa

44


1

ll

Lita ProctorHMP

The Microbiome andImmunotherapy

>1014 microorganisms in GIT making us 90% bugs and 10% “us”!


Composition and luminal concentrations of dominant microbial species in various regions of the gastrointestinal tract.

Gastroenterology 2008 134(2)


The gut microbiota during the human lifespan


Fig. 1 Higher gut microbiome diversity is associated with improved response to anti–PD-1 immunotherapy in patients with metastatic melanoma.

V. Gopalakrishnan et al. Science 2018;359:97-103

Published by AAAS


The Western Microbiota Diverges from That of Non-Western Populations


Checkpoint inhibitors are Expensive

• Nivolumab $13,800/4 wks• Pembrolizumab $12,500/3 wks• Atezolizumab $12,500/3 wks• Nivolumab/Ipilumumab $256,000/1 year


What will be the effect of EndemicInfections ?

More immunogenic tumors leading to increased responses ?

Increased incidence of IRAEs?

Increased activation of microbial and protozoal infections ?

52


Summary• Immune Checkpoint Inhibitors

– Have broad durable activity in a large number of tumors– Predictors of efficacy are complex and not well understood– It is accepted that tumors have to be immunogenic or “inflamed”

with T cell infiltration as a pre-requisite for efficacy– Determinants of inflamed tumors may include tumor genomic profile

and the host microbiome– Combinations with different modalities will be needed to broaden

activity– These combinations are toxic and expensive– Clinical trials need to be performed in less developed countries to

understand toxicity and efficacy patterns


[email protected]

state of the art in development of immunotherapy alex a. adjei€¦ · ©2016 mfmer | slide-3. two...

Documents