silencing the elusive sézary cell past, present, & · pdf filesilencing the...

Tuesday September 28, 2015

Silencing the Elusive Sézary cellPast, Present, & Future

Madeleine Duvic, MD

Prof of Dermatology &

Internal Medicine

Blanche Bender Chair in

Cancer Research

Dept of Dermatology

MD Anderson Cancer Center

Houston, Texas

clinicaloptions.com/oncology

Current Concepts in T-Cell Lymphoma: Applying Evidence to Practice

Clinical Trial or Research Support– Allos/Spectrum, Eisai, Galderma, Kyowa-Kirin, Merck, Millineum, Seattle Genetics, Rhizan, Innate Pharma, Tetrologics, Therakos, Valient

Consultant – Eisai, Galderma, Kyowa-Kirin, Ligand,

Disclosures

Consultant – Eisai, Galderma, Kyowa-Kirin, Ligand, Merck, Millennium, miRNA, Innate

Past Advisory Boards – Allos/Spectrum, Celgene, Eisai, Galderma, Seattle Genetics, Millinieum, Kyowa-Kirin



(1880-1956)

French Dermatologist -

Venereologist.

Described “cellules

monstrueuses”

Albert Sézary

monstrueuses”

(monster cells) in skin

and blood

Am J Dermatopathology

Aug 28(4):357-67, 2006


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeSézary Patient



Variants recognized by Clinical-Pathologic features

Cutaneous T-Cell and NK-Cell Lymphomas

Mycosis fungoides - effector skin memory cells

MF variants and subtypes

Pagetoid reticulosis

Granulomatous slack skin

• WHO-EORTC Classification of CTCL

Willemze R, et al. Blood. 2005;105:3768-3785.

Granulomatous slack skin

Sézary syndrome - central memory T cells – leukemia CD4+CD26- or CD7-

Adult T-cell leukemia/lymphoma ATCL (HTLV-1+)

Primary cutaneous CD30+ lymphoma (ALCL) & Lymphoproliferative disorder (LyP)

Extranodal NK/T-cell lymphoma, nasal type (EBV+)

Primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)

Cutaneous γ/δ T-cell lymphoma (provisional)

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)



� Why are SS patients red and get keratoderma?

� Why are they itch?

� Why is the SS cell nucleus cerebriform?

� Why does photopheresis improve both SS and GVHD?

Questions about Sezary Syndrome

GVHD?

� Can Antiboides or drugs selectively kill malignant T cells?

� Next Gen Sequencing: What are the genetic or epigenetic drivers of T cell proliferation and genomic instability.

� How can we cure SS?


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeClinical Findings of Sézary Syndrome

ectropion

Erythroderma> 80% BSAPruritusPruritus / staph colonization 60%

Keratoderma+ Tinea pedis

CD4+26- or CD4+7-SS by flow cytometrhyB0, B1 250-1000, B2 >1000

Adenopathy – LN0-4Bone marrow +/-



74 yo WF - Sézary Syndrome x 7 years. ECP, bexarotene, & gemcitabine. Red with MRSA sepsis stopped on ampicillin. Ongoing CR x >10 years.

Why are SS patients red?

Baseline Week 8



� Sepsis is most common cause of death in SS patients.

� 1992 - SS cells proliferate in response to bacterial superantigens according to Vb usage.

� 1995 – Catheter associated sepsis in 11/12 ECP pts noting that IV Abs improve EE. Duvic JAAD 1996 35(4):573

•What we learnedStaph and Sézary Syndrome

� 1997 - 76% enterotoxin+ S.Aureus- ETS-1 - TSST- assocVb2 - no fever. Jackow CM, et al. Blood. 1997 Jan 1;89(1):32-40

� 48% of 107 E/SS pts colonized with S.A. or MRSA. 85% decolonized w treatment - Br J Dermatol 2008 Jul;159(1):105-12.

� Standard of care: Atopic skin care w antibiotics improves redness, LDH, SS number, pruritus, and OS



Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC)

Elise Olsen, Eric Vonderheid, Nicola Pimpinelli, Rein Willemze, Youn Kim, Elise Olsen, Eric Vonderheid, Nicola Pimpinelli, Rein Willemze, Youn Kim,

Robert Knobler, Herschel Zackheim, Madeleine Duvic, Teresa Estrach,

Stanford Lamberg, Gary Wood, Reinhard Dummer, Annamari Ranki,

Gunter Burg, Peter Heald, Mark Pittelkow, Maria-Grazia Bernengo, Wolfram

Sterry, Liliane Laroche, Franz Trautinger, and Sean Whittaker, for the

ISCL/EORTC

Revised Blood and Node Staging - 2007



mSWAT Weighing Factors

� % involvement with patch x 1

� % involvement with plaque x 2

� % involvement with tumors (ulcers) x 4

Clinical Evlauation MF/Sézary Syndrome

---------------------------------------------------------

� mSWAT = sum of % lesions x factor

� BSA (body surface area) w/o weighing

� Sezary defined as >80% BSA or T4



� Perivascular infiltrates without diagnostic epidermotrophism

� Sézary cells cerebriform

Leukemic CTCL and Sezary Syndrome are perivascular

� Sézary cells cerebriformmorphology

� CD4+CD26-

� CD4+CD7-

� Central memory T-cells

CD 25 CD 30Diwan AH, Prieto VG, Herling M, Duvic M, Jones D.

Am J Clin Pathol. 2005 Apr;123(4):510-5



% CD4+CD26-

CD4+26- in blood by stage using flow

Bernengo, M.G. The relevance of the CD4+CD26- subset in theidentification of circulating Sézary cells. Br J Dermatol 2001;144:125.


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeP

rob

ab

ility

of

Ove

rall

Su

rviv

al

0.6

0.8

1.0

T1a ( E / N = 14 / 382 )T1b ( E / N = 20 / 139 )T2a ( E / N = 12 / 193 )T2b ( E / N = 51 / 206 )T3 ( E / N = 63 / 136 )T4 ( E / N = 107 / 188 )

Overall Survival by TgrpTalpur & Duvic Clinical Cancer Res 2012 – 1243 MF/SS patients

Patches only T1a or

Plaques T1b < 10%

Years after Diagnosis

Pro

ba

bili

ty o

f O

ve

rall

Su

rviv

al

0 10 20 30 40 50

0.0

0.2

0.4

P-value < .0001

Plaques T1b >10%

T3

T4

Median OS 24 yrs



Pro

babili

ty o

f O

vera

ll S

urv

ival

0.6

0.8

1.0

No ( E / N = 161 / 1062 )Yes ( E / N = 105 / 179 )

Overall Survival by SS

B0-1 <1000 OS 7.6 yr

B2 1000-10,000OS 5.4 yr

B3 >10,000OS 2.4 yr

• Overall survival of 124 Erythrodemic CTCL


Pro

babili

ty o

f O

vera

ll S

urv

ival

0 10 20 30 40 50

0.0

0.2

0.4

P-value < .0001

•Talpur R et al. Clin Cancer Res 18(18):5051-60, 2012..

•Vidulich et al. 2009 Int J. Derm 48(3)243-252

2.5 yrs to 5.4 yrs

OS 2.4 yr

B2


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeWhat Sezary saw What we know now

� Helper Central Memory CD4+CD45R0+CLA+4

� Perivascular infiltrate w/out epidermotropism

� Clonal TCR rearrangements

� Abnormal karyotypes� Abnormal karyotypes

� Th2 cytokines, T-Plastin, Twist, CCR4, CXCR3. KIRDL2, Foxp3, IL2R, Jak/stat5, IL31 itch

� Accumulation – loss of fasinduced apoptosis.

� Role of epigenetics HDACi


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeWhat antigens do T cells encounter?

� T-cells see peptides on dendritic cells in skin, LN

� CLASS 2 Antigens/APC

– HLA-DR 5 –SS OR= 3

– DQB1*03 – SS OR = 4.7

Polyclonal Expansion of Vβ-bearing CD4+ T cells

– DQB1*0502 w SS

– OR= 7.75

� Drug – HCTZ, SSI, gleevec, anti-convulsants

Jackow et al. J Invest Dermol

1996 Sept;107(3):373-6.

Jahn-thigh et al Cancer



� PHOTOPHERESIS – Edelson- first immunotherapy 1988

� Denileukin diftitox - first fusion toxin – 1990s

� Bexarotene (Targretin) - first rexinoid in man 1990s

� Vorinostat first histone deacetylase inhibitor in man

� Romidepsin second HDACi, Belinostat (PTCL)

FDA Approved Therapies

� Romidepsin second HDACi, Belinostat (PTCL)

� Topical Nitrogen mustard in gel base – 2014

� Radiation – electron beam – lower doses 4 x 2, 12 v 36 Gy

� Not approved: Topical Steroids, topical retinoidsaoralsoriataine, tazarotene, UVA and PUVA phototherapy, Interferons, methotrexate, TRL agonists, PD1/PDL1



� Palliative skin directed care: culture for Staph, antibiotics, moisturize and use topical steroids wet wraps, NB-UVB, PUVA, TBSEB

� Itching: gabapentin – opiate antagonists

� First line: Rooks combination immunomodulatorytherapy: photopheresis, bexarotene +/- interferon alpha or gamma, GM-CSF, avoid po stds

Treatment of E-CTCL and SS

alpha or gamma, GM-CSF, avoid po stds

� Second line: HDAC-Inhibitors: Romidepsin, pentostatin, targeted therapies, antibodies (CCR4, CD52,CD30), TBSEB, chemotherapy

� allogeneic SCT ––TBEB + non-ablative allo SCT 75% CRs in SS- submitted JCO

Olsen et al J Am Acad Dermatol 64(2):352-404, 2/2011.



SystemicTreatments

CR%

ORR (PR + CR)

Interferon +/- ECP 20-40 50-80

Bexarotene 5 50

Methotrexate low dose Unk 33-58

Comparison of Systemic Therapies

Methotrexate low dose Unk 33-58

Methotrexate high dose 64 82

Denileukin diftitox 10 44

Vorinostat 0 30

Romidepsin 6 34

Pralatrexate 6 45

Li JY, et al. Cancer Management Res. 2012;4:75-89.

Drews RE J Clin Oncol. 2012;30:4064-4070.



Th1 Th2

Cytokine modulation

Dendritic cell (DC) differentiation

Immunostimulation

CD8+ Cytotoxic T cells

Anti-tumor(L-CTCL)

mDC

Proposed Mechanisms of Action of ECP

How can photopheresis work in SS and GVHD?

Dendritic cell (DC) differentiationImmunosuppression

CD4+ T-regs

Anti-inflammatory

GVHD, autoimmune disorders,

transplantation

Plastic

Monocyte DC

pDC

Shiue et al, JID, 2013 Aug;133(8):2098-100



Monocytoid CD11c+ DCs increase in GVHD & SS Plasmacytoid DC CD123+ up in GVHD, down in SS

Shiue L, Ni X et al, JID, 2013 Aug;133(8):2098-100.


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeDC ratios change in opposite directionsin GVHD & SS after ECP treatment

Shiue L, Ni ,X et al, JID, 2013 Aug;133(8):2098-100.

Allogeneic Stem Cell Transplantation for Cutaneous T-cell Lymphoma: Updated results from a single centerUpdated results from a single center

Journal of Clinical Oncology

First 19 patients

Update on 48 patients from

2001 to present



Age (y), median (range) 51.5 years (19-72 years)

Sex Male 22 (46%)

Female 26 (54%)

Ethnicity Caucasians 33 (69%)

African American 11 (23%)

Demographics of 48 allo SCT patients

Hispanics 4 (8%)

Clinical and PathologicDiagnosis

Sezary Syndrome 17

MF with LCT 24

SS + LCT 7

Stage IVA LN+ or IIB 4 nodal; 1 tumor

Folliculotropic MF 4



Parameter Patients (N=48)

Median Therapies 6 ( range 2-11)

Bexarotene 31 (65%)

Prior systemic Therapies

Bexarotene 31 (65%)

Interferon 24 (50%)

ECP 20 (42%)

Chemotherapy 32 (67%)

TBSEB 43 (90%)


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeOverall Complete Response 58% (28 of 48)Relapse rate 33% (16 of 48) Mortality rate 44% (21/48)

Clinical Variant

N Responders

58%

(28/48)

Relapsed

33% (16/48)

Non-engraftment

8% (4/48)

Dead/Alive

44% (21/48)

SS 14 11 79% 3 21% 3/11

LCT 16 9 56% 4 25% 3 19% 6/10

SS + LCT 9 4 44% 5 56% 4/9

IVA

(LN+)

IIB

4

1

2 40% 2 40% 1 20% 1/4

Fol -MF 4 2 50% 2 50% 2/2



0.

60

.8

1.

0

Pro

ba

bil

OS PFS

Overall and Progression−Free Survival all 48 pts from Transplant date - 4 yr OS 53%

0 2 4 6 8 10 12

0.

00

.2

0.

4

Years

Pro

ba

bil

ity



ORR 34% (6 CRs) in 95 treated patients

� Time to response 2 mos, duration 15 months

� 40% (38 pts) >50% decrease in mSWAT or EE

� 43% had improved pruritus

� 39% OR in 37 pts with B1 or B2 involvement

� 31% (4 of 13) w B2 responded

Pan Pan histone deacetylase inhibitor Romidepsin

� 31% (4 of 13) w B2 responded

Whittaker et al JCO October 2010 vol 28, 4485

erythroderm

pruritus

Skin mswat

nodes



TARGETED FUSION PROTEINS:

� Denileukin diftox – IL2 plus diptheria toxin –now E7777

� CD3 –diptheria toxin – phase I/II clinical trial

TARGETED ANTIBODIES

Targeted Therapies

� Brentuximab vedotin–anti-CD30-auristatin E conjugate P3

� CCR4 defucosylated Antibody - approved for ATL Japan

� Anti -KIR3DL2 (LPH-4012) killer immunoglobulin like MHC receptors - Orphan status 2014, trial 2015

� Targeting miRNA 155

Duvic et al. Blood 2010 and JID 2013

Kaplan et al Expert Rev Hematol. 2014 Aug;7(4):481-93



ONTAK Mechanism of Action - Ex-Vivo Studies

Targeted Therapies

Binding Endocytosis Translocation Toxin Release

1. IL-2 receptor

binding

2. Internalization

viaendocytosis

3. Active

fragmentreleased into

cytosol

4. Inhibition of

protein synthesis, resulting in cell

death



Pivotal Phase 3 Trial of Denileukin Diftitoxin CTCL: Response Rates by Stage

44

50

40

30

Re

sp

on

se

(%

)

CR/CCR

PR

3032

Targeted Therapies

20

10

0

Re

sp

on

se

(%

)

199

25

IB16

IIA10

18%

18

III11

21

IIB19

11 20

13.4

IV15

6.6

Olsen et al. J Clin Oncol. 2001;19:376–388.



ALK-negative ALCL

MF

CCR4 Receptor on CD4+ lymphocytes

MF (transformed)

PTCL-U

Ishida T, et al. Clin Cancer Res. 2004 Aug 15;10(16):5494-500.



Asn297

: N-acetylglucosamine

: bisec GlcNAc

: Mannose

: Galactose

: Sialic acid

KW-0761: Humanized Defucosylated Monoclonal Antibody “Mogamulizumab”Enhanced ADCC

(Potelligent®)

Fucos

e

Targeted Therapy to CCR4 chemokine

: Sialic acid

：：：： Fucose

• Antibody backbone lacks Antibody backbone lacks Antibody backbone lacks Antibody backbone lacks fucosefucosefucosefucose• Leads to an increase in ADCC Leads to an increase in ADCC Leads to an increase in ADCC Leads to an increase in ADCC

activity compared to conventional activity compared to conventional activity compared to conventional activity compared to conventional antibodiesantibodiesantibodiesantibodies

Ishida et al, Clin Cancer Res 2003;9:3625


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeHumanized Anti-CCR4 Antibody: KW-0761Mogamulizumab (KW-0761)

Schedule q two weeks then q week IV

• Phase I/II studies in ATLL in Japan – approved

• Phase I/II US and Phase III Randomized Trial

Yano H, et al. Clin Cancer Res. 2007;13:6494-6500.Duvic M et al. Blood - March 19; 125 (12):1883-9

Ligands TARC, MDC

on endothelial cells.

Helper CD4 and T-regs



Case Study: Patient 05-MDACC(MF; Stage IVA ; 4 Prior Therapies)

Mogamulizumab – Anti-CCR4

PretreatmentCourse 1 Day 1

Post Course 6CRCRCRCR---- 3 years 3 years 3 years 3 years



Patient Subgroups ORR

Number of patients

CR PR SD PD

Mycosis Fungoides

(N=21)29% 1 5 11 4

Sezary Syndrome

Results of Phase I/II Multi-center CCR4 Ab trialGlobal Composite Response

Sezary Syndrome

(N=17)47% 1 7 7 2

TOTAL

(N=38)37% 2 12 18 6

• Overall ORR of 37Overall ORR of 37Overall ORR of 37Overall ORR of 37% vs 47% in % vs 47% in % vs 47% in % vs 47% in SézarySézarySézarySézary patients patients patients patients • MultiMultiMultiMulti----center Phase III CCR4 center Phase III CCR4 center Phase III CCR4 center Phase III CCR4 vsvsvsvs vorinostatvorinostatvorinostatvorinostat trial trial trial trial



%CD4+CD26-

CCR4 Antibody normalizes Sézary cells in blood

Absolute

CD3+CD26-0 10

210

310

410

5

CD26

0

102

103

104

105

CD

3

0 102 103 104 105

CD26

0

102

103

104

105

CD

3 CD3+CD4neg

Normal CD3+CD4+

Lymphoma cells



Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sézary syndrome.

Ni X, Jorgensen JL, Goswami M, Challagundla P, Ni X, Jorgensen JL, Goswami M, Challagundla P, Decker WK, Kim YH, Duvic M.

Clin Cancer Res. 2015 Jan 15;21(2):274-85. doi:

10.1158/1078-0432.CCR-14-0830. Epub 2014 Nov 5



0.80

1.20

1.60

22.64

20.00

30.00

40.00

Effects of anti-CCR4 antibody (KW-0761) on regulatory

T cells and natural killer cells in CTCL patients

**

*

0.00

0.40

0.80

Before After Before After

T-regs (%) Foxp3 (fold change)

16.02

4.92

8.70

0.00

10.00

20.00

Before After Before After

NK cells (%) % killing (E:T 50:1)

Xia Ni et al. Clin Cancer Res. 2015 Jan 5;21(2):274-85

% T-regs Foxp3 %NK % Killing



Expression in 33 Patients with Sézary Syndrome

Targeted Therapy: KIR3D2L mAb

Poszepczynska-Guigne, E., J Invest Dermatol 2004;122,820


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeThe different presentations of CTCL

Patch

Patch

Plaque

Woringer-Kolopp DiseasePagetoid reticulosis

Erythrodermic

Tumor

Tumor

Plaque



EpidermotropicLarge cell

Tumor stage

+/- large cell

Large cell

Transformation?

Advanced >IIB: Tumors (LCT), Nodes, Blood, Viscera

Large cell

Spread to Blood

Sezary syndrome

+/- large cell

Systemic Large Cell

Transformation (LN)Refractory

Disease


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeP

rob

ab

ility

of

Pro

gre

ssio

n-f

ree

Su

rviv

al

0.6

0.8

1.0

no ( E / N = 80 / 414 )yes ( E / N = 63 / 105 )

Progression-free Survival by LCT


Pro

ba

bili

ty o

f P

rog

ressio

n-f

ree

Su

rviv

al

0 10 20 30 40 50

0.0

0.2

0.4

P-value < .0001

N=105 w LCT

N=415 wo LCT


Current Concepts in T-Cell Lymphoma: Applying Evidence to PracticeAnalysis of Mutations associated with Large Cell Transformation

Large Cell Transformation is associated with

Significant decrease overall survival in all LCT patients & in African AmericansAmericans

Mutations in

T53, PD1, CCR4



SP

Z-0

30

SP

Z-0

14

SP

Z-0

36

SP

Z-0

20

SP

Z-0

12

SP

Z-0

13

SP

Z-0

31

SP

Z-0

25

§

SP

Z-0

01

SP

Z-0

10

SP

Z-0

32

SP

Z-0

34

SP

Z-0

33

SP

Z-0

16

SP

Z-0

23

§

SP

Z-0

21

SP

Z-0

06

SP

Z-0

19

SP

Z-0

02

SP

Z-0

18

SP

Z-0

27

SP

Z-0

17

SP

Z-0

07

SP

Z-0

03

SP

Z-0

29

SP

Z-0

05

SP

Z-0

26

§

SP

Z-0

09

SP

Z-0

28

SP

Z-0

22

SP

Z-0

15

SP

Z-0

11

SP

Z-0

24

§

SP

Z-0

04

¶

SP

Z-0

08

SP

Z-0

37

SP

Z-0

38

Histopathological data

Age <60 ≥60 ≥70 ≥80

Race W B H AI

Stage IVA IVB IB

Gender Male Female

SS origin de novo Pre-MF

LCT Without With

Vital status Alive Dead

� � � �

� � �

� �

Somatic mutationsCCR4

CARD11

FAS

Nonsense

Splicing siteRPS6KA1

ZEB1

Frame-shift

TP53

ARID1A

RHOA

0

5

10

15 M

uta

tio

n p

er

Mb

Silent

Nonsilent

Genomic Exon Sequencing

2 mutations/Mb

Mutations

heterogeneous

Tumor suppressors

P53 �

� � �

� � �

�

�PCDHB6

PLCG1TNFRSF1B

ZFYVE26

CD28

USH2AROBO2

CSMD1

ZFHX4

FAT4

D2HGDH

ING5

XIRP2

FAT1FAT3

PCLOPRDM16

CBX3MED22WBP1L

WNK2

TNFAIP3

CSMD3

Copy-neutral LOH

Missense

Missense expressed

TRIO

Homozygous deletion

Focal copy number alterationsLOH

Missense COSMIC

Fusion transcriptsIn-frame fusion

CDKN2A

PDCD1

0

0.2

0.4

0.6

0.8

1 DNM

T>G

T>C

T>A

C>T

C>G

C>A

Indel

P53

LOH – blue

UV Signature

Methylation



1p

36

.1

2q

37

.3

7p

14

.1

7q

34

14

q1

1.2

9p

21

.3

MYC STAT5A/5B

ARID1

A

PDCD1

D2HGD

H

ING5

CDKN2A

CDKN2BTRG TRB

TCF3

19

p1

3.3

TP53

17

p1

3.1

10

p1

1.2

3

10

q2

3.3

1

FAS

ZNF438

ZEB1

100%

50%

0%

0%

50%

100%

TRA

DLEU1

DLEU2

13

q1

4.2

The Sezary Genome -Loss or Gain Chromosome& Expression by RNA seq



G1

S G2

M

G0

G1/S Checkpoint

G2/M Checkpoint CDK2

CCNE1

RB1 E2F

CCND1

CCND3

CDK4

MYC

CDKN2A

FD-58%

M-3%

M-3%

BA-39%

M-3% BD-39%

TP53 M-30%

FD-3% BD-72%

E2F

HIC1 HOXA9

ARID1A FD-33% M-8%

CDKN1A

FD-11%

CDK1

CCNB1

ATR M-5%

ATM

CDC25C

CDC25A/B

M-3%

CHEK1/2

CREBBP M-3%

EP300 M-3%

M: Somatic mutation FD: Focal deletion BA: Broad amplification BD: Broad deletion F: Gene fusion

Up: Upregulated %: Percentage of cases altered

RPS6KA1

FD-33%

ARID3A

Up (56%, 5.5-fold)

a

PATHWAYS TO THE FUTURE

�

EP300 M-3% %: Percentage of cases altered BD-41%

α β

TCR/CD3

CD

4

PT

PR

C

CD

28

CT

LA

4

PD

CD

1

CA

CN

M-42% F-5% FD-36%

ICO

S

PI3K M-13% F-3%

Cell proliferation Survival

ZAP70

GRB2

RAS

M-5%

Ca2+

NFAT

M-8%

NFAT AP-1

Ca2+

Ca2+

ITPR1/3

M-13%

CAMK2

M-8%

CREB

LA

T

SOS1

PLCG1

M-3%

M-11%

LCP2

ITK PIP2

DAG

M-3%

PTPN11

PTPN6

LCK

CDC42

MAPK8

M-3%

JUN

M-5%

ATF2

PRKCQ

MAP3Ks

M-13% IKBKB

M-3%

CARD11

M-13%; F-3%

BCL10

MALT1

NF-κB

RAC

Up (88%, 8.6 fold)

Up (53%, 5.4 fold)

F-3% F-3%

Up (53%, 5 fold)

b



� Why is the SS cell nucleus cerebriform?

� Why are SS patients red? Staph toxins? AMPs?

� Why do they acquire keratoderma? 60% Tinea+

� Why are they cold? Vasodilation, VEGF, low TSH

� Why to they itch? opiate receptor mediated, IL-31

Questions Remaining

� Why to they itch? opiate receptor mediated, IL-31 from CCR4+ cells killed by HDAC-inhibitors

� What genes or epigenetic changes drive T cell proliferation? Making progress – T cell signalling

� Can we cure SS? 79% SS cured with TBSEB and non-ablative allogeneic transplant and target therapy for others.



� Spatz & Anderson Foundations, Blanche Bender Chair, NCI, Dermatology Foundation, companies for financial support for trials and translational research.

� Lab and Clinical Research: Xia Ni, Lisa Shuie, R Talpur, C-L Zhang, Clinical Research Fellows, Derm Residents, medical students.

Acknowledgments

� Baylor Genome Center- D. Wheeler, Linghua Zhang

� CTCL family – colleagues/friends throughout the world who take care of CTCL patients and support each other: USCLC, EORTC, ISCL, CLIC

Naomi Kanof Lecture75th SID Meeting May 8, 2015

Silencing the Sézary cellPast, Present, & Future

Madeleine Duvic, MD

Prof of Dermatology &

Internal Medicine

Blanche Bender Chair in

Cancer Research

Dept of Dermatology

MD Anderson Cancer Center

Houston, Texas



� Attended NYU medical school, mentored by DrSulzberger and became editor of the Journal of Investigative Dermatology x 17 years. She married a lawyer, had two children in Washington DC.

� Dedicated to her patients, Chief of Pediatric

Who was Naomi Kanof?

� Dedicated to her patients, Chief of Pediatric Dermatology at Washington Hosp Center

� She knew political figures – Wilber Mills’ Fanny Fox. She and Scoop Jackson raised funds for Sulzberger chair & start the Military Dermatology Program- John Stanley first job.

� (S. Katz, unpublished data)



� Duke Medical School - Duke Triple Threats: Lowell

Goldsmith, Gerald Lazarus, S. Pinnell & Brian

Jegasothy. Master clinicians: J Lamar Callaway, Robert

Gilgor, Mike Tharp, Janet Hickman.

� Elizabeth Kanoff (Naomi’s cousin) taught “how to run an

office and divert curbside consults.”

Pathway Analysis

office and divert curbside consults.”

� NIH immunology 3rd year elective- Fauci, Anderson,

Waldmann. First scientific paper – improved the lives

of NZB/W mice w estrogen inhibitor. Saw first SS pt.

� Clinical Research can help more people than a private

practice and collaborate with interesting people.

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