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

Haibo Sun, Thomas G Martin, John Marra, Denice Kong, Jonathon Keats, Sandrine Macé, Marielle Chiron, Jeffrey L Wolf, Jeffrey M Venstrom, Raja Rajalingam, Haibo Sun, Thomas G Martin, John Marra, Denice Kong, Jonathon Keats, Sandrine Macé, Marielle Chiron, Jeffrey L Wolf, Jeffrey M Venstrom, Raja Rajalingam

Abstract

Background: Phase 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.

Methods: We 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.

Results: Patients 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.

Conclusions: Our 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 number: NCT01749969.

Keywords: genetic markers; immunity; immunotherapy; innate.

Conflict of interest statement

Competing interests: HS: no relationship to disclose. TGM: research funding: Sanofi. JM: no relationship to disclose. DK: no relationship to disclose. JK: no relationship to disclose. SM: employee of Sanofi. MC: employee of Sanofi. JLW: consulting or advisory role: Onyx/Amgen, Takeda, and Celgene. JMV: no relationship to disclose. RR: research funding: Sanofi; consulting or advisory role: CareDx.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Killer-cell immunoglobulin-like receptors (KIR) haplotypes vary in gene content. Map of group A and B KIR haplotypes. Inhibitory KIR genes are depicted in white boxes with their specific human leukocyte antigen (HLA) class I ligands. Activating KIRs are shown in dark boxes. Hatched boxes represent pseudogenes or KIR genes with no apparent function. The centromeric and telomeric half are marked.
Figure 2
Figure 2
The Kaplan-Meier curves showing the impact of specific killer-cell immunoglobulin-like receptors (KIR)+human leukocyte antigen (HLA) combinations on progression-free survival (PFS) of relapsed or refractory multiple myeloma (RRMM) patients with RRMM treated by isatuximab+lenalidomide+dexamethasone (A, B). Patients carrying KIR3DL2+HLA-A3/11+ had significantly prolonged PFS compared with the patients missing those combinations (A). In contrast, patients with KIR2DL1+HLA-C2C2+ had significantly reduced PFS compared with patients missing this combination (B). Mechanistic studies confirm the role of these KIR+HLA interactions in modulating isatuximab-dependent natural killer (NK) cytolysis of MM cells (C, D). Multiple myeloma (MM) cells expressing HLA-A3/11 (ANBL6 expresses HLA-A3, and KMS18 expresses HLA-A11) showed a significantly improved isatuximab-dependent NK cytolysis compared with those that were negative for HLA-A3/11 (SKMM2 and JK6L) (C). All these four MM cell lines (ANBL6, KMS18, SKMM2, and JK6L) coexpress HLA-C1C1 and HLA-Bw4I80 ligands. The MM cell lines expressing HLA-C2C2 (Karpas620 and ARD) were resistant to isatuximab-dependent NK cytolysis compared with the MM cell lines (AMO1, KAS61, KMS20, and XG2) that are negative for HLA-C2C2 (D). These six MM cell lines (Karpas620, ARD, AMO1, KAS61, KMS20, and XG2) co-express HLA-Bw4T80 ligand. The cognate HLA class I ligands of the effector NK cells are given in parenthesis. Data provided in (C) and (D) represent the mean±SD of 11 independent experiments.
Figure 3
Figure 3
Impact of FCGR3A genotypes on progression-free survival (PFS) and isatuximab-dependent natural killer (NK) cell-mediated cytotoxicity. The Kaplan-Meier curves showing PFS with patients having a high-affinity FCGR3A-158VV/VF genotype compared with the patients having low-binding FCGR3A-158FF genotype (A). Six multiple myeloma (MM) cell lines expressing a similar set of human leukocyte antigen class I ligands (C1C1+Bw4+) were treated with and without isatuximab (10 µg/mL), and then exposed to primary NK cells carrying either homozygous FCGR3A-158VV or FF genotype. Effector NK cells with FCGR3A-158VV mediate greater isatuximab-dependent antibody-dependent cell-mediated cytotoxicity compared with the NK cells expressing FCGR3A-158FF (B).
Figure 4
Figure 4
The Kaplan-Meier curves showing the impact of specific killer-cell immunoglobulin like receptors (KIR)+human leukocyte antigen (HLA) and FCGR3A gene polymorphisms on progression-free survival (PFS) of patients with relapsed or refractory multiple myeloma treated by isatuximab+lenalidomide+dexamethasone. Patients carrying KIR3DL2+HLA-A3/11+ plus FCRG3A-158V (A) or KIR2DL3+HLA-C1C1+ (B) had significantly prolonged PFS compared with the patients missing those combinations.

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