Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma

Abstract

BackgroundPhase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy.MethodsWe characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response.ResultsPatients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF.ConclusionsOur results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.Trial registration numberNCT01749969.

KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer

“…Interestingly, the KIR3DL2 carrier patients in our cohort also had the FcγR3A V-allele, and, accordingly, exhibited greater ADCC efficiency than the KIR3DL2+ and FcγR2A F/F individuals. These data agreed with the findings described by Sun et al, that reported a higher NK cell-mediated cytolysis of Multiple Myeloma cells dependent on the mAb isatuximab in the presence of the KIR3DL2+, HLA-A3/A11+, and FcγR3A V markers ( 34 ).…”

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

“…The functional interaction of KIR3DL2 with HLA-A3/11 is poorly studied, and this interaction is weaker than the other KIRs with HLA-C and HLA-B ligands ( Dohring et al, 1996 ). Since KIR3DL2 is a framework gene present in all individuals, the functional role of the receptor is arguably dependent on its interaction with HLA-A3/11 ( Sun et al, 2021 ). Although the mechanism of anti-SARS-CoV2 activity rendered by inhibitory KIR3DL2 + HLA-A3/11 + interaction is unclear, our results indicate that NK cell recognition through 3DL2 + HLA-A3 + interaction may trigger more robust NK cytolysis when HLA-A3 is presented with viral peptides ( Hansasuta et al, 2004 ).…”

“…The control samples were HLA typed using a commercially available Sequence-Specific Oligonucleotide hybridization kit (LABType ® SSO, One Lambda, Canoga Park, CA). We described the KIR genotyping ( Sun et al, 2021 ) and HLA genotyping protocols by NGS ( Kong et al, 2021 ) and SSO ( Sun et al, 2021 ) elaborately in our previous publications.…”

Inhibitory receptors for HLA class I as immune checkpoints for natural killer cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy

“…Trastuzumab mediates ADCC against HER2 overexpressing cell lines which is irrespective of the NK cell donor genotype KIR-ligand interaction [7] Phase IIb clinical trial including 57 patients with (RR)MM receiving Isatuximab-Lenalidomide-Dexamethasone combination, supported by in vitro cytotoxicity assays Most prolonged PFS with patients carrying KIR3DL2 + HLA-A3/11 + and FCGR3A 158 V polymorphism combination (Not due to education), which was recapitulated in in vitro ADCC assays. Suppressed NK cell ADCC with KIR2DL1 + HLA-C2 + interaction KIR-ligand interaction [46] In vitro study using NK cells expanded on K562-mbIL15-41BBL cells.…”