ArticleJournal for immunotherapy of cancer2021
Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01749969 (A Phase 1b Study of SAR650984), which is not on this map. Cited by 11 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1b Study of SAR650984 (Anti-CD38 mAb) in Combination With Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma
Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer.Frontiers in immunology · 2021Trial
- Advances in natural killer cell immunotherapy for hematologic malignancies.Cancer biology & therapy · 2026Review
- Single-cell RNA sequencing reveals immune regulatory mechanisms and molecular therapeutic strategies in the microenvironment of multiple myeloma.International journal of surgery (London, England) · 2026Article
- Global patterns of KIR genotype diversity reflect human migration and regional differences.Frontiers in immunology · 2026Article
- Review
- Natural killer cells affect the natural course, drug resistance, and prognosis of multiple myeloma.Frontiers in cell and developmental biology · 2024Review
- CD16American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2023Article
- BDL-SP: A Bio-inspired DL model for the identification of altered Signaling Pathways in Multiple Myeloma using WES data.American journal of cancer research · 2023Article
- Activated Mast Cells Combined with NRF2 Predict Prognosis for Esophageal Cancer.Journal of oncology · 2023Article
- Targeting CD38 in Neoplasms and Non-Cancer Diseases.Cancers · 2022Review
- Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19.Frontiers in genetics · 2022Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
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 NUMBER: NCT01749969.
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