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State of the Art in Development of Immunotherapy
Alex A. AdjeiESMO AFRICACape TownFebruary 15, 2018
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DISCLOSURE OF INTEREST
Alex A. Adjei
Institutional financial interests :
Clinical trial Funding : MSD, Piqur, Macrogenics, Kura
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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
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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
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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.
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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.
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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.
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Lesson 1The Checkpoint Inhibitors really work !!!
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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)
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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
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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
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Lesson 2
There are durable responses – Could some patients with metastatic disease be cured ?
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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
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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
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Lesson 3
• How long should we treat ?
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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
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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
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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
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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
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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
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AFB, PCR +ve for M. tuberculosis
Diffuse lymphocytic infiltration were in the alveolae
Fujita et al, JTO 2016.
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Can we Identify patients who will benefitfrom immunotherapy ?
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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
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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
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Tumor Mutational Burden (TMB)
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High TMB is associated with response to checkpoint inhibition
DCB: Durable clinical benefit (PR/SD >6months)NDB: No durable benefit
Rizvi. Science 2015
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What mutations to “count” in TMB
SNVs
Synonymous
Non-synonymous
Rizvi. WCLC 2017
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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
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S. Peters et al, AACR 2017
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Cellular infiltrates within the Tumour microenvironment
Kerkar & Restifo. Cancer Res 2012
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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
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Inhibiting PD-1-mediated adaptive immune resistance
Melanoma cellor tumor macrophage
Interferons
Anti-PD-1Anti-PD-L1
Tumeh et al. Nature 2014
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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
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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
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Planned and ongoing trials
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Pertinent issues withImmunotherapy in Africa
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1
ll
Lita ProctorHMP
The Microbiome andImmunotherapy
>1014 microorganisms in GIT making us 90% bugs and 10% “us”!
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Composition and luminal concentrations of dominant microbial species in various regions of the gastrointestinal tract.
Gastroenterology 2008 134(2)
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The gut microbiota during the human lifespan
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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
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The Western Microbiota Diverges from That of Non-Western Populations
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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
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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 ?
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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
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