Harnessing NK cell immune functions for immunotherapeutic - - PowerPoint PPT Presentation

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Harnessing NK cell immune functions for immunotherapeutic - - PowerPoint PPT Presentation

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Harnessing NK cell immune functions for immunotherapeutic interventions in HIV-1 infection Christian Krner, Ph.D. Research Department Virus Immunology Heinrich Pette Institute Leibniz Institute for Experimental Virology AREVIR-Meeting

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Harnessing NK cell immune functions for immunotherapeutic interventions in HIV-1 infection

Christian Körner, Ph.D.

Research Department Virus Immunology Heinrich Pette Institute Leibniz Institute for Experimental Virology

AREVIR-Meeting – 3.05.2019

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NK cells in viral infections

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Orange, Microbes and Infection (2002)

NK cell deficiencies

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NK cells in natural HIV-1 infection

4 time since seroconversion (y) Fraction of AIDS-free individuals

Martin et al., Nature Genetics (2002)

HLA-Bw4-Iso80 HLA-Bw4 KIR3DL1 KIR3DS1

Martin et al., Nature Genetics (2007)

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HIV-1 immune evasion

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  • Description of KIR-associated amino acid polymorphisms in HIV-1 infected individuals.
  • HIV-1 selects variants to evade NK-cell-mediated immune pressure.
  • NK-cell-mediated control of HIV-1 seems to be genetically hard-wired (KIR/HLA-I).
  • In principle, NK cells have the ability to control HIV-1 infection.

Alter et al. Nature, 2011 Hölzemer/Thobakgale et al., PLoS Medicine (2015)

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How can we utilize NK cell functions to control HIV-1 infection?

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Adapted from Vivier et al., Nature Reviews Immunology (2012)

How do NK cells work?

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NK cell functions

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NK cell

Anti-viral activity Tumor surveillance Shaping adaptive immune responses

Cytotoxicity (granzymes, perforin) ADCC

DC T cell

Killing of immature DC (“DC-editing”) Differentiation (IFN-y)

T cell

Elimination of T cells IFN-y, TNF-a, MIP-1α, MIP-1β

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NK cell functions

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NK cell

Anti-viral activity Tumor surveillance

Cytotoxicity (granzymes, perforin) ADCC IFN-y, TNF-a, MIP-1γ, MIP-1β

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Antibodies

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NK cell

KIR

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CD16 NKG2A Inducing „missing self“

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IPH2102 Monalizumab Inducing ADCC using bNAbs

ClinicalTrials.gov ID: NCT02018510 ClinicalTrial.gov ID numbers: NCT02399917, NCT02599649, NCT02252263, NCT02481297, NCT01687387, NCT01714739, NCT01592370,

  • NCT01750580. Trials.gov ID numbers:

NCT02921685, NCT02643550

+ _ _

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Enhancing NK cell functions

Adapted from Ram et al., JLB (2019)

ClinicalTrials.gov ID: NCT02077868, NCT02200081 and NCT02668770 ClinicalTrials.gov ID: NCT01885897

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Gary Larson

Addressing the mammoth in the room

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Paust, Blish, Reeves, JV (2017)

NK cell memory

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Summary

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  • NK cells are promising target for immunotherapies.
  • Enhancement of NK cell-mediated antiviral functions can be achieved by …
  • 1. Blockade of inhibitory receptors to induce “missing-self”
  • 2. Induction of ADCC using bNAbs (“combined arms”)
  • 3. Stimulation of NK cells through cytokines
  • 4. Eliciting “memory-like” NK cells responses through vaccination
  • 5. CAR NK cells
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Thank for you attention

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Research Department Virus Immunology Heinrich Pette Institute Leibniz Institute for Experimental Virology

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Acknowledgements

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Leidos Biomedical Research Inc. Frederick National Laboratory for Cancer Research Mary Carrington Pat Martin University Medical Hospital Hamburg- Eppendorf Julian Schulze zur Wiesch University Medical Hospital Bonn Jacob Nattermann Jürgen Rockstroh Institute of Molecular Virology, Univerity Hospital of Ulm Frank Kirchhoff Daniel Sauter

Institute for Transfusion medicine