cd38: from the lab to the clinic and back again - · pdf filec d38: from the lab to the clinic...

CD38: from the lab to the clinic and back again

NIELS VAN DE DONK

Department of Hematology, VU University Medical Center Amsterdam

Papendal, January 2017

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=6Fwd-rSLizDLHM&tbnid=-l8-zBxpTQmU8M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.vumc.com%2Fbranch%2Fcca%2F&ei=0p0QVMWWNcrmPKLRgJgG&bvm=bv.74894050,d.bGQ&psig=AFQjCNF1xmiM3xeyW4MhTUXDV39FQPSvag&ust=1410461505666510

Immuno-therapy in multiple myeloma

DC, dendritic cell; IMiD, immunomodulatory agent; I-O, immuno-oncology; mAb, monoclonal antibody. 1. Finn OJ. Ann Oncol. 2012;23(suppl 8 ):viii6-viii9. 2. Mellman I et al. Nature. 2011;480:480-489.

Immunotherapy1,2

Passive (Designed to act on the tumor)

Antitumor mAbs Adoptive

Active (Designed to act on the immune system itself)

Therapeutic cancer vaccines

I-O therapies

• Cell-based • DC-based cancer

vaccines • Single antigen/peptide-

based

• Immune effector cell modulators

• Checkpoint Inhibitors

• Co-stimulatory agonists

Unspecific

• Cytokines • Interleukins • Interferons

• IMiDs

• Tumor-directed mAbs • Anti-CD38

• Cell therapies • Adoptive T-cell

therapy

VU University Medical Center Amsterdam The Netherlands

CD38 as a Therapeutic Target High expression on myeloma cells combined with its

role in cell signaling suggested CD38 as a potential therapeutic antibody target for treatment of multiple myeloma (MM)

1. Malavasi F, et al. Physiol Rev. 2008;88(3):841-886. 2. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488. 3. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477. 4. Deaglio S, et al. Leuk Res. 2001;25(1):1-12.

8

https://en.wikipedia.org/wiki/File:Protein_CD38_PDB_1yh3.png


Generation of the first CD38 mAb for MM

Human Ig transgenic mice were immunized with recombinant CD38 protein and CD38-transfected NIH 3T3 cells

Generation of hybridomas (fusion of mice spleen/lymph node cells with SP2/0 MM cells)

Testing of 42 anti-CD38 mAbs in CDC assays only one mAb was capable to induce CDC this antibody was selected for further testing=daratumumab

De Weers et al. J Immunol. 2011;186:1840–8.

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Finvestinutrecht.com%2Futrecht_science_park&ei=ShZJVYupH9DvaPjwgagD&bvm=bv.92291466,d.d2s&psig=AFQjCNHITl11RS6fGEQV8JKNbufZHBRQlQ&ust=1430939585724859


Laboratory evaluations Clinical evaluation -Phase 1 -Phase 2 -Phase 3

Clinical management

•Activity •MoA

•Mechanisms of resistance •MoSynergy

•IRR •Interference in blood transfusion tests

•Interference in SPEP/IFE

http://www.google.nl/url?url=http://www.mitearrest.com/press.html&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwjKxo7ag7nMAhVBLMAKHdJUA9YQwW4IJjAE&usg=AFQjCNFSkZJ0N8lSmcWAlCp0v_nBeoUvZg

http://www.google.nl/url?url=http://www.123rf.com/photo_10743936_96-wells-plate-with-solution.html&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwjbsc7sg7nMAhWiCMAKHcNwBEMQwW4IGDAB&usg=AFQjCNET_QdP1R9nEHK183JLimSANNYuWw

http://www.multivu.com/players/English/7624051-janssen-darzalex-fda-approval/gallery/image/6bf1b553-0506-4372-a277-52d68f71b971.HR.jpg


Mechanisms of action


Van De Donk et al. Blood 2016;127:681-695

mAbs targeting cell surface Ags


…..but, CD38 is rapidly reduced on MM cells, also in patients with deep and durable responses

Start

Inf 10 PD PD+6M

0

500

1000

1500

MFI

CD

38

*******

**

Patient 1: Patient 2: B

Before start of treatment During daratumumab treatment before the 10th infusion At the time of progressive disease

CD38

Cou

nts Patient 3: Patient 4:

Nijhof Blood 2016

Bone marrow MM cells


CD38 is rapidly reduced on MM cells also in patients with deep and durable responses

Nijhof Blood 2016

Start Inf 2 Inf 4 Inf 8 Inf 11 PD PD +2M

PD+4M

PD+6M

0

5000

10000

15000

20000

25000

MFI

CD

38

****

**NS

Circulating MM cells


Does DARA also have other effects ?


CD38, also expressed on other cells….

Krejcek ASH 2015 Abstract 3037; Krejcek Blood 2016;128(3):384-94


Tregs

Similar observations with Bregs and MDSCs



Decrease in CD38+ Tregs



Functional relevance


VU University Medical Center A t d Th N th l d

Multifactorial mechanism of action

Krejcek Blood 2016;128(3):384-94


Daratumumab: waterfall plot

16 mg/kg: ORR 36%2

1. Lokhorst HM, et al. Oral presentation at ASCO 2014 (Abstract 8513). 2. Lokhorst HM, et al. N Engl J Med 2015;373:1207-19.

1


How to improve CD38 mAb monotherapy results rationale of combinations

16 mg/kg: ORR 35%

Keats Blood 2012;120:1067-1076. Morgan GJ, et al. Nature Rev Cancer 2012; 12, 335-348. Lokhorst HM, et al. N Engl J Med 2015;373:1207-19.


Daratumumab-combinations based on preclinical evaluations

IMID-based PI-based IMID/PI-based +alkylator ATRA ….

Van De Donk Blood 2015


LENALIDOMIDE

Van De Donk et al. Cancer Manag Res 2012; 4:253–268.


DARA and Len: synergistic killing of MM cells from a LEN/Bort-double refractory MM patient

Nijhof et al. Clinical Cancer Res 21(12); 2802–10.


SCR

EEN

RAN

DO

MIZ

E

1:1 Until progression

DRd (n = 286) DARA 16 mg/kg IV:

weekly for 8 weeks, then q2w for 16 weeks, then

q4w thereafter; Lenalidomide 25 mg PO:

d 1–21 per cycle; Dexamethasone 40 mg PO:

weekly

Rd (n = 283) Lenalidomide 25 mg PO:

d 1–21 per cycle; Dexamethasone 40 mg PO:

weekly

aOn daratumumab dosing days, dexamethasone was administered 20 mg premed on Day 1 and 20 mg on Day 2; DRd, daratumumab, lenalidomide, and dexamethasone; SC, subcutaneous; q2w, every 2 weeks; q4w, every 4 weeks; Rd, lenalidomide and dexamethasone. Dimopoulos et al. Presented at EHA 2016 (Abstract LB2238), oral presentation. Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331.

Multicenter, randomized (1:1), open-label, active-controlled phase 3 study

Key eligibility criteria

• RRMM • ≥1 prior line of

therapy • Prior lenalidomide

exposure, but not refractory

• Patients with creatinine clearance ≥30 mL/min

Stratification factors • No. prior lines of therapy • ISS stage at study entry • Prior lenalidomide Cycles: 28 days

Statistical analyses • 295 PFS events: 85% power for 7.7

month PFS improvement • Interim analysis: ~177 PFS events

Primary endpoint • PFS Secondary endpoints • TTP • OS • ORR, VGPR, CR • MRD • Time to response • Duration of response

Pre-medication for the DRd treatment group consisted of dexamethasone 20 mga, paracetamol, and an antihistamine

POLLUX (MMY3003) phase III trial design Preclinical data led to Phase 2 GEN503 and Phase 3 POLLUX studies


POLLUX: Efficacy in the 1 to 3 prior lines subgroup

77%

50%

18-month PFSa

Rd

DRd

Median: 18.4 months

HR: 0.36 (95% CI, 0.26-0.49; P <0.0001)

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 18 21 27

264 272

231 253

193 238

169 227

149 217

122 187

5 15

0 1

Rd DRd

No. at risk Months 24

0 0

15

45 79

16

32

31

26

24 12

23

8

0

10

20

30

40

50

60

70

80

90

100

DRd(n = 267)

Rd(n = 257)

sCR

CR

VGPR

PR

≥VGPR: 78%c

ORR = 77%b

≥VGPR: 46%

≥CR: 47%c ≥CR:

20%

ORR = 94%b

P <0.0001

OR

R, %

Responses continue to deepen in the DRd group with longer follow-up


Determinants of response


Determinants of efficacy: Patients treated in GEN501 or Sirius

< PR ≥ PR0

50000

100000

150000

200000

MFI

CD

38

P = 0.005

Nijhof IS, et al. Leukemia 2015; 29, 2039–2049; Nijhof IS, et al. Blood 2016 128:959-970.


Complement inhibitors

< PR ≥ PR0

5000

10000

15000

20000

25000

MFI

CD

46

NS

< PR ≥ PR0

10000

20000

30000

40000

50000

MFI

CD

55

NS

< PR ≥ PR0

5000

10000

15000

MFI

CD

59

NS

Start Inf 10 PD0

50

100

150

200

250

MFI

CD

55

NS**

Start Inf 10 PD0

50

100

150

200

250M

FI C

D59

NS*

Start Inf 10 PD0

100

200

300

400

MFI

CD

46

NS

NS

ATRA upregulates CD38 expression on MM cells

s o lv e n t c o n tro l

A TR A 0

6 0 0

1 2 0 0

1 8 0 0

MF

I C

D3

8

* * *


Nijhof IS, et al. Leukemia 2015; 29, 2039–2049.


A T R A0

2 0 0

4 0 0

6 0 0

MF

I C

D5

5

*


A T R A0

4 0

8 0

1 2 0

MF

I C

D5

9

* *


A T R A0

5 0 0

1 0 0 0

1 5 0 0

MF

I C

D4

6

n s

DARA PLUS ATRA

0 0 .3 1 3 .3 1 00

2 0

4 0

6 0

D a ra tu m u m a b (µ g /m l)

CD

C (

%)

D A R AD A R A + A T R A

* * ** * * * * * * * * * * *

0 0 .0 1 0 .1 1 1 00

2 0

4 0

6 0

D a ra tu m u m a b (µ g /m l)

AD

CC

(%

)

D A R AD A R A + A T R A

* * *




-56

days0 21 3528 4942 56

BLIATRADARA

tumorinoculation

scaffoldimplantation

PBMC-T

-56

2 1 2 8 3 5 4 2 4 9 5 6

0

5 0 0 0 0

1 0 0 0 0 0

1 5 0 0 0 0

c o n tro l (1 )

D A R A (3 )

A T R A + D A R A (4 )

A T R A (2 )

d a y s

rela

tive

tu

mo

r g

row

th (

%)

** ** ******

***

DARA PLUS ATRA



DARA + ATRA at the time of Progressive Disease

Starttreatment

PD PD +48h

ATRA

0

300

600

900

1200

1500

MFI

CD

38

**ns

Starttreatment

PD PD +48h

ATRA

0

200

400

600

800

MFI

CD

55* ns

ns

Starttreatment

PD PD +48h

ATRA

0

50

100

150

200

MFI

CD

59

**

ns

Nijhof Blood 2016


DARA PLUS ATRA Phase 1/2 study of ATRA + DARA in patients who do not

respond to daratumumab as single agent or who progress during daratumumab therapy

https://clinicaltrials.gov/ct2/show/NCT02751255?term=ATRA+daratumumab&rank=1


DARA-NIVO study: RRMM starting Q2 2017

Anti-CD38: Daratumumab

Anti-PD1: Nivolumab

IMID: Lenalidomide

+

Anti-CD38: Daratumumab

Anti-PD1: Nivolumab + + + Steroid:

Dexamethasone



Clinical management

•Activity •MoA








Infusion reactions with DARA

Van De Donk 2017, submitted; Van De Donk Blood 2016; Van de Donk Immunol Rev 2016


Van De Donk Blood 2016; Van De Donk Immunol Revs 2016; Oostendorp Transfusion 2015


Van De Donk CCLM 2016; McCudden CCLM 2016


DIRA

Van De Donk CCLM 2016; McCudden CCLM 2016



Clinical management

•Activity •MoA








Acknowledgements VUmc MM groep Inger Nijhof Berris van Kessel Kris Frerichs Patty Bosman Laurens Franssen Yvette Vleeschdraager Lisa Holthof Esther Drent Maria Themeli Henk Jan Prins Renee Poels Ruud Ruiter Susan van Veen Regina de Jong Afroditi Katsaroy Tamas Csikos Hilma van der Horst Claudia Stege Jakub Krejcek Henk Lokhorst Tuna Mutis Richard Groen Sonja Zweegman

VUmc hematologie Henk lokhorst Josee Zijlstra Otto Visser Martine Chamuleau Jeroen Janssen Arjan van de Loosdrecht Ellen Meijer Mari van Wondergem Jackeline Cloos Linda Smit Angel Draeger Richard Groen Tuna Mutis Gerrit Jan Schuurhuis Eva de Jong Marjolein Donker Cleo van Rooijen Linde Morsink Fellows Gert Ossenkoppele Sonja Zweegman

VUmc Hem Research Nurses Louise Nieuwenhuis Eveline Sollner Yvonne den Hartog Sandy Kruyswijk Astrid Vervoort … VUmc Hem datamanagement Saida Absalah Tineke Kruijt Marjan Leisink Maartje Blok Tanja Roosma Geraldine Droog … Maaike Leidekker VUmc hematologie dagbehandeling VUmc hematologie 3B VUmc hematologie labs UMCU Immunologie Andries Bloem Jeroen van Velzen Henny Otten

HOVON MM groep European Myeloma Network UMCU hematologie Janssen Kate Sasser, Tine Casneuf , Homer Adams, Chris Chiu

Genmab Jan van de Winkel, Paul Parren, Jeroen Lammerts van Bueren

cd38: from the lab to the clinic and back again - · pdf filec d38: from the lab to the clinic...

Documents