HarnessingAdap-veNKCellsinCancerImmunotherapy

Karl-JohanMalmberg,

MD.PhD.Prof.

“Immunotherapyagainstcancerislikedryinganoceanwithanhairdryer”

Challenge

To decipher the cellular and molecular mechanisms underlying immune failure and exploit this knowledge to convert clinical non-responders to responders

Regula-onofNKcellfunc-onbykillercellimmunoglobulin-likereceptors(KIR)

MalmbergandLjunggren,NatureReviewsImmunology2007

Virus infection / Tumor transformation

Normal cell

Cancer/ Infected cell

Transformation/Infection

VariegatedKIRexpressionconfertoleranceandbroadspecifici-esinmissing-selfrecogni-on

Respondingcell

Haploidentical NK cell therapy - Preliminary results from a Phase I/II trial at the Karolinska Institute

NKcelltherapyacrossHLAbarriers–missingselfinthenewhost!

Kill

ProtocolDesign–RefractoryAMLorMDS

Escala-ngdoseoftotallymphoidirradia-on

(TLI)andaddi-onofCyclosporineA

3

3

3 Infusion of over night

IL-2 activated Haploidentical NK cells

6/16pa-entsreachingCRorPRbecomingeligibleforstemcell

transplanta-on

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

u ¤ è RAEB-2

u ¤ è MDS/AML

u ¤ ¢ è AML

u ¤ � ★ NK ✝

u � ★ ¢ è u CR/mCR/CRistart

u ¤ ✳ ✝ u mCR/PRstart

u � ★ NK ✝ u Stabledisease

u � ✝ � Responseend

✝ è Continuedresponse

✝

✝ ¤ SCT

u � ✝ ¢ DLI

✝ ★ Chemotherapy

u ✝ NK 2ndNK-treatment

✝ ✳ PTLDinCR

✝ ✝ Diseased

1year 2years 3years

Non-responder Responder0

20

40

60

80

100

Freq

uenc

y liv

e lin

- CD

34+ 0.0480

Reduc-onofCD34+blastcounts

Role for NK cells in the therapeutic effect?

NKcellmicro-chimerismatday7-14correlateswithclinicalresponses

Per

cent

of p

atie

nts

(%)

p=0.03

Non-responder Responder

Non-responder Responder0

10000

20000

30000

40000

GEO

M o

n liv

e lin

-C

D34

+CD

123+

CD

45R

A+ 0.0177

Immunoedi-ng–higherlevelsofHLAclassIonresidualblastsinresponders

Non-responder Responder0

200

400

600

800

Geo

M H

LA-E

on

live

lin-C

D34

+CD

123+

CD

45R

A+

0.0025

HLAclassI HLAE

Harnessing the power of adaptive NK cells

CyTOF:105

Horowitz et al., Science Transl. Med. 2013

NotallNKcellsareequal

CMVSCT

CD8 NK

Beziat et al., Blood, 2013b

Beziat et al., Blood, 2013a

Björklund et al., , Blood, 2010

Andersson et al., Blood, 2009

Björkström et al., Blood, 2010

Björkström et al., Blood, 2012

CNV

80

60

40

20

Blackrepertoires:CMV-nega-veindividualsn=48

Donor#164,C2C2CMV-posi-ve

Donor#59,C1C1CMV-posi-ve

PercentofN

Kcells

CMVisassociatedwithaclonal-likeexpansionofadap-veNKcells

BeziatV.etal.Blood2013

Expandingtumor-reac-veNKcells

CD2providessignal2inan-body-drivenadap-veNKcellresponses

Signal1Signal2

Expansionplagorms

Balancingnumbersandspecificity

Karolinska Institutet Per Ljungman Eva Hellström-Lindberg Petter Höglund Klas Kärre Sten Linnarsson Björn Önfelt Sören Lehman Björn Wahlin Hans-Gustaf Ljunggren Univ. of Minnesota Jeffrey Miller Sarah Cooley Univ. of Cambridge John Trowsdale James Traherne Stanford University Amir Horowitz Peter Parham

Oslo University Hospital (OUH) and UiO Johanna Olweus Arne Kolstad Eivind Hovig Andreas Brecht Harald Stenmark Kjetil Taskén Funding KI/SLL Theme Centers: Regenerative Medicine and IMTAC The Swedish Research Council The Swedish Cancer Foundation The Swedish Children's Cancer Foundation The Swedish Royal Society of Medicine Oslo University Hospital The Norwegian Cancer Society KG Jebsen Foundation

Malmberg group Karolinska Institutet Marie Schaffer Monika Enqvist Andreas Björklund Vivien Beziat (Paris) Lisa Liu Ebba Sohlberg Aline Pfefferle Oslo University Hospital Julie Hoel Merete Wiiger Vincent Yi Sheng Oei Eivind Ask-Hæggernes Jodie Peter Goodridge Kishan Chudasma Michelle Sætersmoen Trevor Clancy Benedikt Jakobs Axel Berg-Larsen

Acknowledgements