PMID- 34272304 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20220111 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 7 DP - 2021 Jul TI - Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma. LID - 10.1136/jitc-2021-002958 [doi] LID - e002958 AB - 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. CI - (c) 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. FAU - Sun, Haibo AU - Sun H AD - Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Martin, Thomas G AU - Martin TG AD - UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. FAU - Marra, John AU - Marra J AD - UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. FAU - Kong, Denice AU - Kong D AD - Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Keats, Jonathon AU - Keats J AD - Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA. FAU - Mace, Sandrine AU - Mace S AD - Translational and Experimental Medicine, Sanofi Research & Development, Vitry-sur-Seine, France. FAU - Chiron, Marielle AU - Chiron M AD - Translational and Experimental Medicine, Sanofi Research & Development, Vitry-sur-Seine, France. FAU - Wolf, Jeffrey L AU - Wolf JL AD - UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. FAU - Venstrom, Jeffrey M AU - Venstrom JM AD - UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. FAU - Rajalingam, Raja AU - Rajalingam R AUID- ORCID: 0000-0001-8821-7877 AD - Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA rajalingam.raja@ucsf.edu. LA - eng SI - ClinicalTrials.gov/NCT01749969 GR - P30 CA082103/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antibodies, Monoclonal, Humanized) RN - R30772KCU0 (isatuximab) SB - IM MH - Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use MH - Humans MH - Immunotherapy/*methods MH - Killer Cells, Natural/*immunology MH - Multiple Myeloma/*drug therapy PMC - PMC8287616 OTO - NOTNLM OT - genetic markers OT - immunity OT - immunotherapy OT - innate COIS- 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. EDAT- 2021/07/18 06:00 MHDA- 2022/01/12 06:00 PMCR- 2021/07/16 CRDT- 2021/07/17 05:44 PHST- 2021/06/07 00:00 [accepted] PHST- 2021/07/17 05:44 [entrez] PHST- 2021/07/18 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/07/16 00:00 [pmc-release] AID - jitc-2021-002958 [pii] AID - 10.1136/jitc-2021-002958 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Jul;9(7):e002958. doi: 10.1136/jitc-2021-002958.