new insights on merkel cell carcinoma€¦ · new insights on merkel cell carcinoma emory melanoma...
TRANSCRIPT
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New Insights on Merkel Cell Carcinoma
Emory Melanoma / Skin Cancer Symposium
Saturday, Feb 27, 2016; Emory Conference Center35 min talk + 10 min questions
Clinic:
Seattle Cancer Care Alliance
Fred Hutchinson Cancer
Research Center
Paul Nghiem, MD, PhDProfessor & Head, UW Dermatology/Medicine & Pathology
George F. Odland Endowed Chair in Dermatology
Research:
Univ of WA
Lake Union Campus
UV DNA Damage/Cell cycle
Merkel cell carcinoma
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Overview
• Pathogenesis & the Merkel polyomavirus– Risk factors
– Viral oncogenesis
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Overview
• Pathogenesis & the Merkel polyomavirus– Risk factors
– Viral oncogenesis
• Tumor / viral immunity– Humoral and cellular immunity
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Overview
• Pathogenesis & the Merkel polyomavirus– Risk factors
– Viral oncogenesis
• Tumor / viral immunity– Humoral and cellular immunity
• Therapy– Current & future immune-based therapies
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Why is MCC important?
• More lethal than melanoma– ~40% mortality (~15% for melanoma)
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Why is MCC important?
• More lethal than melanoma– ~40% mortality (~15% for melanoma)
• Reported incidence increasing– Quadrupled since 1986
– Currently ~2,000 new cases/yr in USA
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Why is MCC important?
• More lethal than melanoma– ~40% mortality (~15% for melanoma)
• Reported incidence increasing– Quadrupled since 1986
– Currently ~2,000 new cases/yr in USA
• Optimal therapy is unique among skin CAs– Proper tx is relatively benign, effective
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What is a Merkel Cell?Friedrich Merkel, 1875 Mechanoreceptors in basal
layer of epidermis?
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What is a Merkel Cell?
copyright: Paul Nghiem & Paul Quade, www.EchoMedicalMedia.com
Friedrich Merkel, 1875 Mechanoreceptors in basal
layer of epidermis?
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What is a Merkel Cell?
• Essential for light touchMaricich, et al, Science, 2009
• Derived from epidermis (not neural crest)
Van Keymeulen, et al, J Cell Biol, 2009
Morrison, et al, Dev Biol, 2009
copyright: Paul Nghiem & Paul Quade, www.EchoMedicalMedia.com
Friedrich Merkel, 1875 Mechanoreceptors in basal
layer of epidermis?
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Merkel cell CA: clinical appearance (easy to miss)
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Clinician’s Impression at the Time of
Bx in 106 MCC pts
BENIGN 56% • Cyst/Acneiform lesion 32%
• Lipoma 6%
• Dermatofibroma 5%
MALIGNANT 36% • Non-melanoma skin CA 19%
• Lymphoma 6%
• Metastatic Carcinoma 2%
• MCC 1%
Indeterminate 8% • "Nodule" Heath, JAAD, 2008
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"Perinuclear dot pattern"
of cytokeratin-20
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MCC Reported Incidence is Rising
1500 new
cases/yr
in USA
in 2005(NCDB data)
Lemos & Nghiem
JID 2007
CK20
antibody
Many cases
‘missed’
1600 new
cases/yr
in USA
in 2006
(SEER data)
Albores-Saavedra
J Cut. Path 2009
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Increase in Risk Factors
• Prolonged sun exposure
– 98% Caucasian; Latitude associated; sun-
exposed skin
• Immune suppression (HIV, SOTR, CLL)
• Age > 50
Paulson & Nghiem,
unpublished
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Clinical appearance (easy to miss)
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Clinical Presentation
Generic description: "Firm papule / nodule, often red or purple"
We wanted more concrete data…
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A: Asymptomatic
E: Expanding rapidly
I: Immune Compromised
O: Older than 50
U: UV-exposed, fair skin
89% of MCCs: ≥ 3 features
(sensitive, NOT specific!)
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A: Asymptomatic
E: Expanding rapidly
I: Immune Compromised
O: Older than 50
U: UV-exposed, fair skin
89% of MCCs: ≥ 3 features
(sensitive, NOT specific!)
If red, rapidly growing,
non-tender nodule on
sun-exposed skin of
pt over 60:
? biopsy
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MCC Presenting Site
In 138 patients
Heath, JAAD, 2008
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Skin: Primary MCC (n=
123)
Nodal Presentation (n=15)
(no primary)
thought experiment...
Assuming there is palpable
nodal disease...
better to have a primary or not?
MCC Presenting Site
In 138 patients
Heath, JAAD, 2008
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2010 AJCC
Staging System
Replaced 5
conflicting staging
systems...
How does one stage an MCC patient?
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Bianca Lemos, MD
2010 AJCC
Staging System
Replaced 5
conflicting staging
systems...
How does one stage an MCC patient?
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AJCC MCC Staging System (2009)
– Stage I: Local, ≤ 2cm
• Ia: Nodes negative by path exam
• Ib: Nodes not clinically detectable
– Stage II: Local, > 2cm
• IIa: Nodes negative by path exam
• IIb: Nodes not clinically detectable
• IIc: Primary tumor invading bone/muscle/fascia/cartilage
– Stage III: Regional Nodal Disease
• IIIa: Nodes pos by path exam and not clinically detectable
• IIIb: Nodes clinically detectable; in-transit metastasis
– Stage IV: Distant Metastatic Disease
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How predictive was the
7th Edition system?
Analysis with an
independent
(subsequent) cohort
Can we make it better?
published 2009
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0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10 11
Local disease (n=213; MCC-specific survival)M
CC
-specific
surv
ival (%
)
Time from diagnosis (years)
IA (n=112)
IB (n=48)
IIA (n=32)
IIB (n=21)
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0
25
50
75
100
0 1 2 3 4 5 6 7 8
Nodal and distant disease (n=215; MCC-specific survival)M
CC
-specific
surv
ival (%
)
Time from diagnosis (years)
IIIA (n=78)
IV (n=26)
IIIB (n=111)
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0
25
50
75
100
0 1 2 3 4 5 6 7 8
Nodal and distant disease (n=215; MCC-specific survival)M
CC
-specific
surv
ival (%
)
Time from diagnosis (years)
IIIA (n=78)
IV (n=26)
IIIB (n=111)
known or unknown primary?
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0
25
50
75
100
0 1 2 3 4 5 6 7 8
MC
C-s
pecific
surv
ival (%
)
Time from diagnosis (years)
IIIB Known Primary Lesion
(n=49)
IIIB Unknown Primary Lesion
(n=62)
Univariate analysis by competing risks regression:
HR 0.31; p<0.01; 95% CI 0.16 – 0.60
Multivariate analysis by competing risks regression:
(controlling for age at dx, sex, and immune suppression)
HR 0.43; p=0.04; 95% CI 0.20 – 0.94
IIIB Patients by Primary Lesion Status (n=111; MCC-specific survival)
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0
10
20
30
40
50
60
70
80
2 year overall survival(Tarantola et al; n=50)
5 year MCC-specific survival(Seattle; n=104)
5 year MCC-specific survival(Busam et al; n=115)
% S
urv
ival
Unknown primary(57%)
Unknown primary(76%)
Known primary(36%) Known primary
(33%)
“Unknown primary” lesion better survival across independent cohorts
Unknown primary(65%)
Known primary(28%)
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Positive lymph node
Poorly functioning immune cells cannot eliminate the primary tumor
Primary tumor
Positive lymph node
Poorly functioning
immune cells
Among Stage IIIB Patients the Presence or Absence of a Primary Matters
Known primaries
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Functional killer T cells secrete effector cytokines or molecules to destroyed the primary tumors.
These patients do much better!!
Unknown primaries
Positive lymph node
Poorly functioning immune cells cannot eliminate the primary tumor
Primary tumor
PrimaryTumorgone
Positive lymph node
Positive lymph node
Poorly functioning
immune cells
Highly functioning
immune cells
Among Stage IIIB Patients the Presence or Absence of a Primary Matters
Known primaries
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The immune system likely mediates
regression of primary tumors
0%
20%
40%
60%
80%
100%
Immune Suppressed(n = 11 )
Not ImmuneSuppressed
(n = 92)
% w
ith
Un
kn
ow
n P
rim
ary
p < 0.0001(Fisher’s exact)
66%
0%!!
IIIb cases:
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The immune system likely mediates
regression of primary tumors
0%
20%
40%
60%
80%
100%
Immune Suppressed(n = 11 )
Not ImmuneSuppressed
(n = 92)
% w
ith
Un
kn
ow
n P
rim
ary
p < 0.0001(Fisher’s exact)
66%
0%!!
IIIb cases:
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Bottom line on initial therapy...
Surgery & radiation:
>95% of patients ‘free of
detectable disease’...
but
MCC recurs in nearly half
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Bottom line on initial therapy...
Surgery & radiation:
>95% of patients ‘free of
detectable disease’...
but
MCC recurs in nearly half
Metastatic MCC chemotherapy (‘small cell regimen’)
- shrinks MCC in most cases
- over half progress by 3 mos...
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Chemotherapy & metastatic MCC
53% of patients ‘respond’...
Half progress by 93 days after starting chemo
(Quite toxic therapy...unsatisfactory results...need options!)
Iyer, et al, in preparation
PFS after 1st line chemo
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Given links to immune suppression, UV...
how does MCC arise?
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Moore/Chang
(KSHV)
Present in 8/10
MCCs
Validated in
dozens of studies
Virus (MCPyV) is
extremely
common!
Schematic ofMCPyV genome
A new human virus that causes cancer (in 2008)
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Adapted from Bhatia/Afanasiev, et al, Curr Oncol Rep, 2011
Virus on us all yet only
1 in 3000 will get MCC…how?
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Adapted from Bhatia/Afanasiev, et al, Curr Oncol Rep, 2011
What are mutation patterns in virus-pos vs virus-neg tumors?
Virus on us all yet only
1 in 3000 will get MCC…how?
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3 studies in late 2015...
genetic mutations in virus-pos & virus-neg MCC...
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3 studies in late 2015...
genetic mutations in virus-pos & virus-neg MCC...
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3 studies in late 2015...
genetic mutations in virus-pos & virus-neg MCC...
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49 MCCs...
Goh, et al. 2015.
Oncotarget
“MCC-Low”“MCC-High”
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49 MCCs...
Goh, et al. 2015.
Oncotarget
“MCC-Low”“MCC-High”
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49 MCCs...
Goh, et al. 2015.
Oncotarget
“MCC-Low”“MCC-High”
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Goh, et al. 2015.
Oncotarget
Viral status
greatly affects
mutation
frequency
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Goh, et al. 2015.
Oncotarget
Viral status
greatly affects
mutation
frequency
100-fold
difference
between
MCC-Lo &
MCC-Hi
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Goh, et al. 2015. Oncotarget
Virus-negative MCCs ‘neoantigens’
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PDL1-pos (‘immune visible’) tumors
have more mutations
Wong, et al. 2015.
Cancer Res.
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PDL1-pos (‘immune visible’) tumors
have more mutations
Wong, et al. 2015.
Cancer Res.
Virus-neg tumors
may be
immunogenic...
We will return to
this!
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Humoral immunity: a powerful biomarker
Kelly Paulson, MD, PhD Will Simonson,MD, PhDMark Wener, MDDenise Galloway, PhD Jody Carter, PhD
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Antibodies to T-Ag (not capsid) fall after tx
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Antibodies to T-Ag (not capsid) fall after txCapsid antibodies:>60% of us have them!
T-Ag antibodies:<1% of 530 population controls~50% of newly diagnosed MCCs
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Antibodies to T-Ag (not capsid) fall after txCapsid antibodies:>60% of us have them!
T-Ag antibodies:<1% of 530 population controls~50% of newly diagnosed MCCs
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Antibodies to T antigen reflect disease burden
Paulson, Carter, et al, CA Research, 2010
“This could be clinically useful...”
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Detecting MCC
recurrences using
serology
Paulson, et al, submitted
PPV = 66%
NPV = 97%
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Oncoprotein Ab Positive (n = 114)
Oncoprotein Ab Negative (n = 105)
Competing-risks Regression
Controlling for: Age, Stage, and Sex
p = 0.037
Hazard Ratio = 0.46
95% CI = 0.224 – 0.955
Time after Diagnosis (Days)
MC
C s
pe
cif
ic S
urv
iva
l (%
)MCC Specific Survival by Oncoprotein Ab Titer
590 1 2 3 4 5
0
25
50
75
100
Paulson, et al, submitted
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Oncoprotein Ab Positive (n = 114)
Oncoprotein Ab Negative (n = 105)
Competing-risks Regression
Controlling for: Age, Stage, and Sex
p = 0.037
Hazard Ratio = 0.46
95% CI = 0.224 – 0.955
Time after Diagnosis (Days)
MC
C s
pe
cif
ic S
urv
iva
l (%
)MCC Specific Survival by Oncoprotein Ab Titer
600 1 2 3 4 5
0
25
50
75
100
Sero-neg patients:
follow with scans
Paulson, et al, submitted
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Assay ‘live’ (available) as of January 2014...Run by UW Lab Medicine (50 ul serum)
Cost $200 (very modest vs CT scan)Helps both virus-pos and virus-neg patients...
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Antibodies are useful for tracking MCC...
What are T cells good for?
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Antibodies are useful for tracking MCC...
What are T cells good for?
Survival!!
If CD8+ T cells are moderate or high within tumor,survival is 100% (n=146 patients + n=150 patients)
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killer CD8 T cell
MCC cell
expressing MCPyV protein
How do CD8 T
cells recognize
their target?
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Finding MCPyV-specific T cells
x
xx
x
MCPyVproteome
map
MCPyV-Antigen source
Jayasri Iyer
David Koelle
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Finding MCPyV-specific T cells
x
xx
x
MCPyVproteome
map
MCPyV-Antigen source
95 peptides: covering 389 AA
Persistently expressed in MCCs
Jayasri Iyer
David Koelle
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T cell source
Finding MCPyV-specific T cells
x
xx
x
MCPyVproteome
map
MCPyV-Antigen source
95 peptides: covering 389 AA
Blood “TIL”Persistently expressed in MCCs
Jayasri Iyer
David Koelle
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T cell source
Antigen presenting cells
Finding MCPyV-specific T cells
x
xx
x
MCPyVproteome
map
MCPyV-Antigen source
95 peptides: covering 389 AA
Blood “TIL”
Assay: T cells produce IFN-γ if recognize peptide
Persistently expressed in MCCs
Jayasri Iyer
David Koelle
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95 peptides: covering 389 AA
x
xx
x
MCPyVproteome
map
MCPyV
Persistently expressed in MCCs
First 26 MCPyV epitopes identified from blood and MCC tumors
epitopesdiscovered
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‘Tools’ for MVPyV-specific T cell study
Iyer/Afanasiev et al, CCR, 2011; Afanasiev et al, submitted
Iyer, et al, Clin Ca Res, 2011
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‘Tools’ for MVPyV-specific T cell study
Iyer/Afanasiev et al, CCR, 2011; Afanasiev et al, submitted
Control subjects
(n=10)
% s
ub
jects
with
te
t+T
ce
lls
MCC patients
(n=9)
0%
Iyer, et al, Clin Ca Res, 2011
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Jim Dowdalls/Photo Researchers, Inc
Why do virus-positive tumors grow if patients have virus-specific T cells??
Virus infected cell
CD8T cell
Are virus-specific T cells dysfunctional?
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Acute antigen
exposure
Activated cells, characterized by expression of:
CD28 Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69 Earliest inducible cell surface glycoprotein during T cell activation; plays a role in T cell proliferation
CD137 (4-1BB)
Member of TNF-receptor family; induced by T cell activation; important in T cell proliferation, cytokine secretion and cytotoxicity
CD38 Cyclic ADP ribose hydrolase; marker of T cell activation; functions in cell adhesion, signal transduction and calcium signaling
HLA-DR MHC class-II surface receptor that is upregulated with T cell activation
T cell surface receptor phenotype
reveals functional profile
Adapted from Afanasiev, Nghiem, MCC book chapter
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Acute antigen
exposure
Activated cells, characterized by expression of:
CD28 Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69 Earliest inducible cell surface glycoprotein during T cell activation; plays a role in T cell proliferation
CD137 (4-1BB)
Member of TNF-receptor family; induced by T cell activation; important in T cell proliferation, cytokine secretion and cytotoxicity
CD38 Cyclic ADP ribose hydrolase; marker of T cell activation; functions in cell adhesion, signal transduction and calcium signaling
HLA-DR MHC class-II surface receptor that is upregulated with T cell activation
T cell surface receptor phenotype
reveals functional profile
Adapted from Afanasiev, Nghiem, MCC book chapter
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Chronic antigen
exposure
Acute antigen
exposure
Activated cells, characterized by expression of:
CD28 Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69 Earliest inducible cell surface glycoprotein during T cell activation; plays a role in T cell proliferation
CD137 (4-1BB)
Member of TNF-receptor family; induced by T cell activation; important in T cell proliferation, cytokine secretion and cytotoxicity
CD38 Cyclic ADP ribose hydrolase; marker of T cell activation; functions in cell adhesion, signal transduction and calcium signaling
HLA-DR MHC class-II surface receptor that is upregulated with T cell activation
Exhausted T cells, characterized by prolonged expression of:
PD-1 Programmed death-1; inhibitory T cell receptor (ligands: PD-L1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and effector functions
CTLA-4 (CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:B7); effectively competes for ligands with CD28 (which has lower avidity than CTLA-4), preventing T cell activation
Tim-3 T cell Immunoglobulin Mucin-3; inhibitory T cell receptor (ligand: galactin-9); leads to decrease in effector T cell function
T
cell
T cell surface receptor phenotype
reveals functional profile
Adapted from Afanasiev, Nghiem, MCC book chapter
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Chronic antigen
exposure
Acute antigen
exposure
Activated cells, characterized by expression of:
CD28 Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69 Earliest inducible cell surface glycoprotein during T cell activation; plays a role in T cell proliferation
CD137 (4-1BB)
Member of TNF-receptor family; induced by T cell activation; important in T cell proliferation, cytokine secretion and cytotoxicity
CD38 Cyclic ADP ribose hydrolase; marker of T cell activation; functions in cell adhesion, signal transduction and calcium signaling
HLA-DR MHC class-II surface receptor that is upregulated with T cell activation
Exhausted T cells, characterized by prolonged expression of:
PD-1 Programmed death-1; inhibitory T cell receptor (ligands: PD-L1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and effector functions
CTLA-4 (CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:B7); effectively competes for ligands with CD28 (which has lower avidity than CTLA-4), preventing T cell activation
Tim-3 T cell Immunoglobulin Mucin-3; inhibitory T cell receptor (ligand: galactin-9); leads to decrease in effector T cell function
Recently activated T cells, characterized by expression of:
Combination of activation and inhibition markers via appropriate immunoregulatory feedback mechanisms
T
cell
T cell surface receptor phenotype
reveals functional profile
Adapted from Afanasiev, Nghiem, MCC book chapter
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Chronic antigen
exposure
Acute antigen
exposure
Activated cells, characterized by expression of:
CD28 Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69 Earliest inducible cell surface glycoprotein during T cell activation; plays a role in T cell proliferation
CD137 (4-1BB)
Member of TNF-receptor family; induced by T cell activation; important in T cell proliferation, cytokine secretion and cytotoxicity
CD38 Cyclic ADP ribose hydrolase; marker of T cell activation; functions in cell adhesion, signal transduction and calcium signaling
HLA-DR MHC class-II surface receptor that is upregulated with T cell activation
Exhausted T cells, characterized by prolonged expression of:
PD-1 Programmed death-1; inhibitory T cell receptor (ligands: PD-L1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and effector functions
CTLA-4 (CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:B7); effectively competes for ligands with CD28 (which has lower avidity than CTLA-4), preventing T cell activation
Tim-3 T cell Immunoglobulin Mucin-3; inhibitory T cell receptor (ligand: galactin-9); leads to decrease in effector T cell function
Recently activated T cells, characterized by expression of:
Combination of activation and inhibition markers via appropriate immunoregulatory feedback mechanisms
T
cell
T cell surface receptor phenotype
reveals functional profile
Adapted from Afanasiev, Nghiem, MCC book chapter
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Are the ‘brakes’ ON in MCC-specific T cells? (compared to other viral responses)
PD-1 Tim-3
Examined ‘exhausted’ PD1+/Tim-3+ cells
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Are the ‘brakes’ ON in MCC-specific T cells? (compared to other viral responses)
Afanasiev et al, Clin Ca Research 2013
PD
1+T
im3
+ (%
po
siti
ve c
ells
)PD-1 Tim-3
(Data from 4-7 MCC patients)
Examined ‘exhausted’ PD1+/Tim-3+ cells
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Afanasiev et al, Clin Ca Research 2013
PD
1+T
im3
+ (%
po
siti
ve c
ells
)PD-1 Tim-3
(Data from 4-7 MCC patients)
Examined ‘exhausted’ PD1+/Tim-3+ cells
Are the ‘brakes’ ON in MCC-specific T cells? (compared to other viral responses)
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Afanasiev et al, Clin Ca Research 2013
PD
1+T
im3
+ (%
po
siti
ve c
ells
)PD-1 Tim-3
(Data from 4-7 MCC patients)
Examined ‘exhausted’ PD1+/Tim-3+ cells
PD-1 & PDL-1 trials
are beginning...
Are the ‘brakes’ ON in MCC-specific T cells? (compared to other viral responses)
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Clinical Trial Indication Target Patient characteristic
Status
IL-12(Oncosec)
Local Injection of IL-12 gene
Injectable lesion Complete
GLA(Immune Design)
Local Toll-like receptor agonist
Injectable lesion Complete
PD-1(Merck)
Metastatic 1st line
PD-1 on T cell No prior systemic therapy
Recruiting
PD-L1(EMD Serono)
Metastatic 2nd line
PD-L1 on Tumor
Progressed after receiving chemo
Recruiting
T cell + PD-L1(EMD + Pfizer)
Metastatic Infuse Virus specific T cells
Virus + MCC ?
4-1BB(Pfizer)
Metastatic CD-137 on T cell
+/- chemo or immune therapy
closed
MCC Clinical Trials Overview
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PDL1 (2nd line) MCC trial:
55 yo woman; primary lesion on chest x 1 year (had metastases at dx)
Failed chemotherapy (Carbo + etoposide)
Large liver mets: 2 x 11 cm
MCPyV-negative
After 4 weeks (2 doses) of PDL1
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Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced
Merkel cell carcinoma
Paul Nghiem1,2, Shailender Bhatia1,2, Adil Daud3, Philip Friedlander4, Harriet Kluger5, Holbrook Kohrt6, Ragini Kudchadkar7, Evan Lipson8, Lisa Lundgren2,
Kim Margolin6, Sunil Reddy6, Erica Shantha1, William Sharfman8, Elad Sharon9, John Thompson1,2, Suzanne Topalian8, Mac Cheever1,2
1) University of Washington 2) Fred Hutchinson Cancer Research Center 3) Univ of California San Francisco 4) Mt Sinai Medical Center 5) Yale University
6) Stanford University 7) Emory University 8) Johns Hopkins University
9) NCI-Cancer Therapy Evaluation Program
European Cancer Congress / ESMO Vienna, Austria
Sunday, September 27th, 2015
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85
Metastatic MCC platin + etoposide
Initial responses common (53%) poor durability:
>50% of patients progress by 3 months
>90% of patients progress by 10 months
Iyer, et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 9091)
Miller, et al, Curr Treat Options Onc, 2013
Median survival = 9.6 months
n = 179
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Trial design: pembrolizumab in MCC
• Strong rationale for anti-PD1 in MCC
– tumor-specific T cells are PD1+, Tim3+
– PDL1 frequent in MCC tumors
• Multi-center (7 sites), single arm, open label, Phase II trial of first systemic therapy
• Primary endpoint: response rate (RECIST 1.1)
86
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Interim results9/18/15
• 24 patients had received at least one dose of pembrolizumab
• 14 patients had at least one post-treatment scan
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Response in MCC target lesions(At first scan, RECIST 1.1 as of 9/18/15 data export)
n = 14
% C
han
ge
in
targ
et
lesio
ns
at
1s
tscan
Progressive disease:
target lesion f/u data
initially not available =
*Complete responses (RECIST 1.1) occurred in lymph nodes that regressed to < 10 mm.
Progression based
on new lesions
Partial Response: 1st
scan data initially not
available, at 2nd scan
was -70% =
* *
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Activity of MK-3475 in patients with advanced MCC(RECIST 1.1 data as of 9/18/15)
Key:
n = 14 includes 2 patients who have PD based only on new
lesions (no f/u data on target lesions currently)
Stable Disease =
Progressive Disease =
Partial Response =
Complete Response =
Progressive disease:
target lesion f/u data
not available =
*Complete responses (RECIST 1.1) occurred in lymph nodes that regressed to < 10 mm.
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Baseline
Response to anti-PD1
Baseline:
- Bulky tumors in pelvis: bladder compression
- Subcutaneous metastases on R leg
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Baseline 3 wks after pembrolizumab
Response to anti-PD1
Baseline:
- Bulky tumors in pelvis: bladder compression
- Subcutaneous metastases on R leg
After 1 dose:
- SQ lesion barely palpable at 3 weeks; biopsy showed. . .
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What happened in the SQ tumor?
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What happened in the SQ tumor?
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Pathologic CR after single dose of pembrolizumab
What happened in the SQ tumor?
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Bladder symptoms resolved
Continues on trial (week 34)
No side effects
Tumors continue to shrink
Partial response on pembrolizumab
Baseline 1st scan (13 wks) after PD1
Bulky pelvic disease:
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Bladder symptoms resolved
Continues on trial (week 34)
No side effects
Tumors continue to shrink
Partial response on pembrolizumab
Baseline 1st scan (13 wks) after PD1
Bulky pelvic disease:
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Conclusions: Pembrolizumab in MCC
• Responses (RECIST 1.1) in 10 of 14 patients (71%)
– More durable than chemotherapy (historical)
• Biomarker studies will address:
– Virus-pos vs. virus-neg MCC responses?
– Does PD-1 increase the number and/or function of preexisting virus-specific T cells in blood/tumor?
(possible in 5 of 15 cases thus far)
• Expansion plans underway...for first line & relapsed disease
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Vision for future MCC management
1. Minimize recurrences
- best initial management (surgery, RT)
- immune-stimulation in ‘adjuvant’ setting...
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Vision for future MCC management
1. Minimize recurrences
- best initial management (surgery, RT)
- immune-stimulation in ‘adjuvant’ setting...
2. If recurrence:
- find early by serology or scans
- reduce tumor & reverse immune evasion
- immune-therapy for long-lasting control...
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Thanks to funding sources
Michael Piepkorn Endowment
Bezos Immune Therapy Fund
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Research scientists: Dafina Ibrani, Lola Yelistratova, Chris Lewis, Ryan Doumani
Undergraduate research assistants & students: Jamil Qazi, Hannah Thomas, Austin Anderson, Christine Ma, Kaushik P, Seesha T, Tessa Marx
Masaoki Kawasumi, Kaifeng HungUV & DNA repair
Lab Team Research fellows:
Jayasri Iyer Erica Shantha Candice Church
Graduate and medical students/doctors: Ata Moshiri, Olga Afanasiev, Natalie Miller, Kelly Paulson, Natalie Vandeven