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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Natural Killer Cells: Receptor Biology takes us to the Clinic The V Foundation May 2 nd, 2016 Michael A. Caligiuri, MD
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Human large granular lymphocytes or natural killer (NK) cells Human NK cell subsets NK cell receptor biology Clinical application of NK cell receptor biology Monocyte NK Cell T Cell 2
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Emerging model for human NK cell subsets: innate immunoregulator, CD56 bright CD56 bright CD16 dim/neg CD94/NK2GA NKRs + KIR +++ CD94/NKG2A TNF-β GM-CSF TNF-α IFN- IL-10 High Cytokine Production C-kit L-selectin high IL-2Rα IL-2/15Rβ cc CD56 bright NK Cell 3
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Secondary Lymphoid Tissue Contributions of the CD56bright NK cells in the human immune response Early ResponseLate Response monokines infection APC NK IFN-γ CD56 bright Fehniger et al, Blood, 2003 APC NK T T MHC TCR IL-12IL-2 IFN-γ IL-12R IL-2R CD56 bright IL-2R 4 T. Fehniger
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Emerging model for human NK cell subsets: innate cytotoxic effector, CD56 dim Low Cytokine Production KIR CD56 dim CD16 bright IL-2/15Rβ cc PEN5/PSGL1 (~70%) Effector Functions +++ ADcCC +++ LAK +++ Natural Cytotoxicity CD56 dim NK Cell NKRs +++ KIR + CD94/NKG2A 5
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Natural killing by an NK cell Getting Inside The Mind Of A Killer 6
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Emerging model for human NK cell subsets: innate cytotoxic effector, CD56 dim Low Cytokine Production KIR CD56 dim CD16 bright IL-2/15Rβ cc PEN5/PSGL1 (~70%) Effector Functions +++ ADcCC +++ LAK +++ Natural Cytotoxicity CD56 dim NK Cell NKRs +++ KIR + CD94/NKG2A 7
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How do inhibitory NKR work? KIR sees and engages MHC Class I molecules and send an inhibitory signal In the absence of an activating ligand KIR prevent autologous NK killing of normal cells KIR 2DL2 Inhibitory Receptor NK HLA-Cw3 SELF Activating Receptor Normal Hematopoietic Stem Cell 8
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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 Target Activating Ligand NK Activating Receptor KIR 2DL2 Inhibitory Receptor HLA-Cw3 9
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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 Lysis Leukemia Target KIR 2DL2 Inhibitory Receptor Activating Ligand Activating Receptor 10
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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 2DL1KIR 2DL2 11
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Human NK cells have KIR that bind to specific EPITOPES that are shared among select MHC class I molecules KIR 2DL2 Cw1 Cw3 Cw7 Cw8 12
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Haplo-mismatch BMT Donor has KIR on some NK cells that bind to Cw3 That KIR is called KIR 2DL2 KIR 2DL2 recognizes an epitope shared by group 1 HLA-C, that includes HLA-Cw1, 3, 7, and 8 If the recipient AML blast lacks group 1 HLA-C, and expresses a ligand to an activating receptor, lysis occurs A24B35Cw2 A3B62Cw3 A24B35Cw2 A1B14Cw2 DonorRecipient (leukemia) 13
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KILL NK Lysis Leukemia Target Activating Receptor Activating Ligand KIR 2DL2 Inhibitory Receptor Haplo-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 A24B35Cw2 A3B62Cw3 HLA-Cw2 (Group 2) Recipient A24B35Cw2 14
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Haplo-mismatch BMT Donor has KIR on some NK cells that binds to HLA-Cw3 That KIR is called KIR 2DL2 KIR 2DL2 recognizes an epitope shared by group 1 HLA-C that includes HLA-Cw1, 3, 7, and 8 If the recipient AML blast expresses group 1 HLA-C, NO lysis A24B35Cw2 A3B62Cw3 A24B35Cw2 A1B14Cw8 DonorRecipient (leukemia) 15
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Human NK cells have KIR that bind to specific EPITOPES that are shared among select MHC class I molecules KIR 2DL2 Cw1 Cw3 Cw7 Cw8 16
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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 expresses HLA-Cw8: engagement of KIR Donor A24B35Cw2 A3B62Cw3 Recipient A24B35Cw2 A24B35Cw8 NO KILL Leukemia Target No Lysis Activating Ligand NK Activating Receptor Inhibitory KIR2DL2 (group 1 specific) HLA-Cw8 (group 1) 17
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Haplo-mismatch BMT Donor A24B35Cw2 A3B62Cw3 Recipient A24B35Cw2 A24B35Cw8 Donor A24B35Cw2 A3B62Cw3 Recipient A24B35Cw2 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 18
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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? 19
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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 transplantations 29 of 60 donor-recipient pairs had appropriate KIR epitope incompatibility 31 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 transplant L. Ruggeri et al, Blood, 2001; Science, 2002; update, 2005 20
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60 AML patients transplanted in CR Leukemia Relapse No KIR Mismatch (n = 31) KIR Mismatch (n = 29) p = 0.002 Years 0246810 0.0 0.2 0.4 0.6 0.8 1.0 12 Event-Free Survival No KIR Mismatch KIR Mismatch p = 0.03 Years 0246810 0.0 0.2 0.4 0.6 0.8 1.0 12 Ruggeri et al, Science 2002, updated 2005 21
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Role of NK cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation Conclusions In 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 direction Additional study of donor versus recipient NK cell alloreactivity in mismatched hematopoietic stem cell transplants has confirmed these results 22
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NK Autologous Leukemia/MM Target Activating Receptor Activating Ligand Blocking KIR in autologous setting for AML and Multiple Myeloma (MM) D. Benson Lysis KILL Benson et al, Clin Cancer Res, 2015 23
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NK GBM Activating Receptor Activating Ligand Adding a Chimeric Antigen Receptor to NK Cells Recognizing EGFR for Glioblastoma Multiforme (GBM) Lysis CAR Han et al, Scientific Reports, 2015 24 EGFR J. Yu
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NK92-CAR-EGFR Cells Reside in situ CNS GBM 25 NK-92 10 × 10 2 × 104 × 10 Patient- Derived GBM Tumor M NC PC brain lung liver BL Sp BM EGFR-CAR 371bp CONFIDENTIAL
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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 % Survival * ** * HBSS NK92-CAR-EV NK92-CAR-EGFR U251 Days U251 Vehicle NK92-CAR-EV NK92-CAR-EGFR
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NK cells: biology to the clinic Summary Human NK cell subsets NK cell receptor biology Clinical application of NK cell receptor biology 27
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caligiurilab.com 28
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