Targeting KIR as a novel approach to improve CAR-NK cell function

Abstract

Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.

Keywords

Killer immunoglobulin-like receptors (KIRs) / natural killer cells (NK cells) / chimeric antigen receptor (CAR) / immunotherapy / CAR-NK cells

References

[1] LiuE,BanerjeeP.Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors.N Engl J Med2020;382:545-53

[2] CurtiA,D'AddioA.Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients.Blood2011;118:3273-9

[3] MillerJS,Panoskaltsis-MortariA.Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.Blood2005;105:3051-7

[4] “CAR-NK”|Recruiting, Active, not recruiting Studies|Cancer. Available from: https://classic.clinicaltrials.gov/ct2/results?term=%22CAR-NK%22&cond=Cancer&Search=Apply&recrs=a&recrs=d&age_v=&gndr=&type=&rslt= [Last accessed on 4 Dec 2023]

[5] DjaoudZ.HLAs, TCRs, and KIRs, a triumvirate of human cell-mediated immunity.Annu Rev Biochem2020;89:717-39

[6] AlgarraI,GarridoF.The HLA crossroad in tumor immunology.Hum Immunol2000;61:65-73

[7] RuggeriL,UrbaniE.Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.Science2002;295:2097-100

[8] FelicesM.Targeting KIR blockade in multiple myeloma: trouble in checkpoint paradise?.Clin Cancer Res2016;22:5161-3 PMCID:PMC5093060

[9] Berrien-ElliottMM,FehnigerTA.Allogeneic natural killer cell therapy.Blood2023;141:856-68 PMCID:PMC10023727

[10] Search Results|Beta ClinicalTrials.gov. Available from: https://clinicaltrials.gov/search?intr=lirilumab&aggFilters=status:act%20rec%20not [Last accessed on 4 Dec 2023]

[11] LiY,WangG.KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape.Nat Med2022;28:2133-44

[12] JolyE.What is trogocytosis and what is its purpose?.Nat Immunol2003;4:815

[13] MiyakeK.The role of trogocytosis in the modulation of immune cell functions.Cells2021;10:1255 PMCID:PMC8161413

[14] HamiehM,CabrioluA.CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.Nature2019;568:112-6 PMCID:PMC6707377

[15] OlsonML,RadhakrishnanSV.Low-affinity CAR T cells exhibit reduced trogocytosis, preventing rapid antigen loss, and increasing CAR T cell expansion.Leukemia2022;36:1943-6 PMCID:PMC9252916

[16] GangM,WongP.CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.Blood2020;136:2308-18 PMCID:PMC7702478

[17] EwenEM,MillerM,CerwenkaA.KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells.Eur J Immunol2018;48:355-65

[18] HeB,PangY.Cytokines induced memory-like NK cells engineered to express CD19 CAR exhibit enhanced responses against B cell malignancies.Front Immunol2023;14:1130442 PMCID:PMC10191231

[19] FontelaMG,PlanesEM.Abstract 887: killer cell immunoglobulin-like receptor 2DL2 (KIR2DL2) immune checkpoint modulates CAR-T cell effector function.Cancer Res2023;83:887

[20] LorenziniT,ObeckH et al.Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy.Br J Cancer2023;129:696-705 PMCID:PMC10421897

[21] LanierLL,WuJ,PhillipsJH.Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.Nature1998;391:703-7

[22] BluntMD.Activating killer cell immunoglobulin-like receptors: detection, function and therapeutic use.Int J Immunogenet2020;47:1-12

[23] SekineT,CaoK.Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation.Blood2016;128:297-312 PMCID:PMC4946205

[24] WeisdorfD,WangT.KIR B donors improve the outcome for AML patients given reduced intensity conditioning and unrelated donor transplantation.Blood Adv2020;4:740-54

[25] BachanovaV,WangT.Donor KIR B genotype improves progression-free survival of non-hodgkin lymphoma patients receiving unrelated donor transplantation.Biol Blood Marrow Transplant2016;22:1602-7 PMCID:PMC4981536

[26] BluntMD,FisherJG.KIR2DS2 expression identifies NK cells with enhanced anticancer activity.J Immunol2022;209:379-90 PMCID:PMC7613074

[27] GrasNavarro A,LeissL.NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.J Immunol2014;193:6192-206 PMCID:PMC4259203

[28] NK cell therapies - artiva. Available from: https://www.artivabio.com/nk-cell-technology/ [Last accessed on 5 Dec 2023]

[29] LemarH,XieM,LazeticS.128 KIR haplotype can inform donor selection production of allogeneic memory-like CAR NK cells for clinical application.J Immunother Cancer2021;9:A137

[30] ZhangM,XuS.Natural Killer Cell Engagers (NKCEs): a new frontier in cancer immunotherapy.Front Immunol2023;14:1207276 PMCID:PMC10450036

[31] NaiyerMM,MagriA.KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C.Sci Immunol2017;2:eaal5296

[32] RettmanP,FultonRJ.Peptide: MHC-based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors.J Immunother Cancer2021;9:e001912 PMCID:PMC8141441

[33] JanCI,CanollP.Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors.J Immunother Cancer2021;9:e003050 PMCID:PMC8524382

[34] TöpferK,MichenS.DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy.J Immunol2015;194:3201-12

[35] GongY,WangJ,GermeraadWTV.Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy.J Hematol Oncol2021;14:73 PMCID:PMC8088725

[36] LiY,MoriarityBS.Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity.Cell Stem Cell2018;23:181-92.e5 PMCID:PMC6084450