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Natural Killer Cells: Receptor Biology takes us to - PowerPoint Presentation

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Natural Killer Cells: Receptor Biology takes us to - PPT Presentation

the Clinic The V Foundation May 2 nd 2016 Michael A Caligiuri MD Human large g ranular lymphocytes or natural k iller NK cells Human NK cell subsets NK cell receptor biology Clinical application of ID: 634214

cell kir hla cells kir cell cells hla receptor b35 activating donor cw2 2dl2 group leukemia recipient car mismatch

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Slide1

Natural Killer Cells: Receptor Biology takes us to the Clinic

The V FoundationMay 2nd, 2016

Michael A. Caligiuri, MDSlide2

Human large granular lymphocytes or natural killer (NK) cells

Human NK cell subsetsNK cell receptor biologyClinical application of

NK cell receptor biology

Monocyte

NK Cell

NK Cell

T Cell

2Slide3

Emerging model for human

NK cell subsets:

innate

immunoregulator

,

CD56

bright CD56bright

CD16dim/neg CD94/NK2GA

NKRs+ KIR+++ CD94/NKG2ATNF-βGM-CSF

TNF-αIFN-gIL-10

High

CytokineProduction

C-kit

L-selectin high

IL-2R

α

IL-2/15R

β

g

c

CD56

bright

NK Cell

3Slide4

Secondary Lymphoid Tissue

Contributions of the CD56bright NK cells in

the human immune response

Early Response

Late Response

monokines

infection

APC

NK

IFN-

γ

CD56

bright

Fehniger

et al, Blood,

2003

APC

NK

T

MHC

TCR

IL-12

IL-2

IFN-

γ

IFN-

γ

IL-12R

IL-2R



CD56

bright

IL-2R



4

T.

FehnigerSlide5

Emerging model for human

NK cell subsets: innate

cytotoxic effector,

CD56

dim

Low

Cytokine

Production KIR CD56dim

CD16brightIL-2/15Rβ

gcPEN5/PSGL1(~70%)Effector Functions+++ ADcCC+++ LAK+++ Natural Cytotoxicity

CD56dim

NK Cell

NKRs

+++ KIR

+ CD94/NKG2A

5Slide6

Natural killing by an NK cell

Getting Inside The Mind Of A Killer

6Slide7

Emerging model for human

NK cell subsets: innate

cytotoxic effector,

CD56

dim

Low

Cytokine

Production KIR CD56dim

CD16brightIL-2/15Rβ

gcPEN5/PSGL1(~70%)Effector Functions+++ ADcCC+++ LAK+++ Natural Cytotoxicity

CD56dim

NK Cell

NKRs

+++ KIR

+ CD94/NKG2A

7Slide8

How do inhibitory NKR work?

KIR sees and engages MHC Class I molecules and send an inhibitory

signal

I

n

the absence of

an activating ligand KIR prevent

autologous NK killing of normal cellsKIR 2DL2Inhibitory ReceptorNKHLA-Cw3SELF

Activating

Receptor

Normal

HematopoieticStem Cell

8Slide9

How do KIR work?

KIR sees and engages MHC Class I molecules and send an inhibitory signal

The KIR inhibitory signal overrides NK killing triggered by activation signal

NO

KILL

Autologous

Leukemia

TargetActivatingLigand

NKActivatingReceptorKIR 2DL2Inhibitory

ReceptorHLA-Cw3

9Slide10

KILL

NK

How do inhibitory NKR work?

Absent or

defective MHC Class

I fails to trigger inhibitory KIR

NK cell kills tumor cell target if tumor expresses ligand to activating receptor

LysisLeukemiaTargetKIR 2DL2Inhibitory Receptor

Activating

LigandActivatingReceptor10Slide11

Human NK cells have KIR that bind to specific EPITOPES that are shared among some but not other MHC class I molecules

Binds HLA

-Cw2, 4, 5, and 6

(Group 2 HLA-C epitopes)

HLA-Cw1, 3, 7, and 8

(Group 1 HLA-C epitopes)

KIR 2DL1

KIR 2DL2

11Slide12

Human NK cells have KIR that bind to specific EPITOPES that are shared among select MHC class I molecules

KIR 2DL2

KIR 2DL2

KIR 2DL2

KIR 2DL2

Cw1

Cw3

Cw7

Cw8

12Slide13

Haplo-mismatch BMT

Donor has KIR on some NK cells that bind to Cw3That KIR is called KIR 2DL2KIR 2DL2 recognizes an epitope shared by group 1 HLA-C,that includes HLA-Cw1, 3, 7, and 8If the recipient AML blast lacks group 1 HLA-C,and expresses a ligand to an activating receptor, lysis occurs

A24 B35 Cw2

A3 B62

Cw3

A24 B35 Cw2

A1 B14

Cw2

Donor

Recipient (leukemia)13Slide14

KILL

NK

Lysis

Leukemia

Target

Activating

Receptor

ActivatingLigandKIR 2DL2Inhibitory

ReceptorHaplo-mismatch BMT

KIR 2DL2 expressed on some donor NK cells recognizes an epitope shared by HLA-Cw1, 3, 7, 8

The AML blast from

recipient

expresses

HLA-Cw2: no

engagement

of KIR

Donor

A24 B35 Cw2

A3 B62 Cw3

HLA-Cw2

(Group 2)

Recipient

A24 B35 Cw2

A24 B35

Cw2

14Slide15

Haplo-mismatch BMT

Donor has KIR on some NK cells that binds to HLA-Cw3That KIR is called KIR 2DL2KIR 2DL2 recognizes an epitope shared by group 1 HLA-C that includes HLA-Cw1, 3, 7, and 8If the recipient AML blast expresses group 1 HLA-C, NO lysis

A24 B35 Cw2

A3 B62

Cw3

A24 B35 Cw2

A1 B14

Cw8

Donor

Recipient (leukemia)15Slide16

Human NK cells have KIR that bind to specific EPITOPES that are shared among select MHC class I molecules

KIR 2DL2

KIR 2DL2

KIR 2DL2

KIR 2DL2

Cw1

Cw3

Cw7

Cw8

16Slide17

Haplo-mismatch BMT

KIR 2DL2 expressed on

donor NK cells

recognizes

an

epitope shared

by HLA-Cw1, 3, 7, 8

The AML blast from recipient expressesHLA-Cw8: engagement of KIRDonorA24 B35 Cw2A3 B62 Cw3RecipientA24 B35 Cw2A24 B35

Cw8

NO

KILL

Leukemia

TargetNo Lysis

ActivatingLigand

NK

Activating

Receptor

Inhibitory

KIR2DL2

(group

1

specific

)

HLA-Cw8

(group 1)

17Slide18

Haplo-mismatch BMT

DonorA24 B35 Cw2A3 B62 Cw3

Recipient

A24 B35 Cw2

A24 B35

Cw8

DonorA24 B35 Cw2A3 B62 Cw3RecipientA24 B35 Cw2A24 B35 Cw2

NO

KILL

Leukemia

Target

No Lysis

NK

Inhibitory

KIR2DL2

(group

1

specific

)

HLA-Cw8

(group 1)

KILL

NK

Lysis

Leukemia

Target

Activating

Receptor

Activating

Ligand

KIR

2DL2

Inhibitory

Receptor

HLA-Cw2

(Group 2)

Activating

Receptor

Activating

Ligand

18Slide19

Relevant clinical issues for haploidentical KIR epitope incompatible transplantation for AML in CR

Do DONOR stem cells, infused without T-cells, get rejected by HOST NK when KIR are incompatible in host vs graft direction?Do DONOR NK cells, upon encountering KIR incompatibility with normal HOST tissues, cause graft versus HOST disease in the absence of T-cells?Do DONOR NK cells, upon encountering KIR incompatibility with HOST leukemia, cause a graft versus LEUKEMIA effect in the absence of T-cells?

19Slide20

Role of NK cell alloreactivity in haploidentical KIR epitope incompatible transplantation for AML in CR

60 HLA haplotype-mismatched, T-cell depleted hematopoietic stem cell transplantations29 of 60 donor-recipient pairs had appropriate KIR epitope incompatibility31 of 60 donor-recipient pairs did not have appropriate KIR epitope incompatibility

No donor graft rejection in KIR mismatch patients

No graft versus host disease in KIR mismatch patients

In vitro analysis of donor NK cell lysis of host target cells was consistent with

rules” up to three months after the transplantL. Ruggeri et al, Blood, 2001; Science, 2002; update, 200520Slide21

60 AML patients transplanted in CR

Leukemia

Relapse

No KIR Mismatch

(

n = 31)

KIR Mismatch

(

n = 29)

p = 0.002

Years

0

2

4

6

8

10

0.0

0.2

0.4

0.6

0.8

1.0

12

Event-Free

S

urvival

No KIR Mismatch

KIR Mismatch

p = 0.03

Years

0

2

4

6

8

10

0.0

0.2

0.4

0.6

0.8

1.0

12

Ruggeri

et

al,

Science 2002, updated

2005

21Slide22

Role of NK cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation

ConclusionsIn mismatched transplants, a clinical graft-versus leukemia effect, independent of T-cell-mediated graft versus host disease, appears to positively impact on relapse rate when NK cell KIR epitope incompatibility is in the graft versus host directionAdditional study of donor versus recipient NK cell alloreactivity in mismatched hematopoietic stem cell transplants has confirmed these results

22Slide23

NK

Autologous

Leukemia/MM

Target

Activating

Receptor

Activating

LigandBlocking KIR in autologoussetting for AML and Multiple Myeloma (MM)

D. BensonLysisKILL

Benson et al, Clin Cancer Res, 201523Slide24

NK

GBM

Activating

Receptor

Activating

Ligand

Adding a Chimeric Antigen

Receptor to NK CellsRecognizing EGFR for Glioblastoma Multiforme (GBM)

LysisCARHan et al, Scientific Reports, 201524

EGFRJ. YuSlide25

NK92-CAR-EGFR Cells Reside in situ CNS GBM

25NK-92

10 × 10

2 × 10

4 × 10

Patient-Derived

GBM Tumor

M NC PC brain lung liver BL

Sp

BM

EGFR-CAR

371bp

CONFIDENTIALSlide26

Single injection of NK92-CAR-EGFR Cells Inhibit GBM Tumor Growth in vivo and Prolong Survival of Mice Implanted with U251 GBM Cells & Primary GBM

26

Primary GBM

NK92-CAR-EV

NK92-CAR

-EGFR

Vehicle

p/s/cm²/

sr

(×10

6

)

NK92-CAR

-EGFR

*

U251

NK92-CAR-EV

Vehicle

*

% Survival

Days

Days

% Survival

*

**

*

HBSS

NK92-CAR-EV

NK92-CAR-EGFR

U251

Days

U251

Vehicle

NK92-CAR-EV

NK92-CAR-EGFRSlide27

NK cells: biology to the clinic

SummaryHuman NK cell subsetsNK cell receptor biologyClinical application of NK cell receptor biology

27Slide28

caligiurilab.com

28