Journal Article
. 2012 Sep; 120(22):4317-23.
doi: 10.1182/blood-2012-06-437558.

A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission

Norbert Vey 1 Jean-Henri Bourhis  Nicolas Boissel  Dominique Bordessoule  Thomas Prebet  Aude Charbonnier  Anne Etienne  Pascale Andre  François Romagne  Don Benson  Herve Dombret  Daniel Olive  
Affiliations
  • PMID: 23002117
  •     139 citations

Abstract

IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.

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Ann Transl Med, 2020 Apr 21; 8(5). PMID: 32309391    Free PMC article.
Review.
PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells.
Silvia Pesce, Marco Greppi, +5 authors, Emanuela Marcenaro.
Front Immunol, 2019 Jun 20; 10. PMID: 31214193    Free PMC article.
Highly Cited. Review.
Killers 2.0: NK cell therapies at the forefront of cancer control.
Jonathan J Hodgins, Sarwat T Khan, +2 authors, Michele Ardolino.
J Clin Invest, 2019 Sep 04; 129(9). PMID: 31478911    Free PMC article.
Highly Cited. Review.
Natural Killer Cells: Tumor Surveillance and Signaling.
Lizeth G Meza Guzman, Narelle Keating, Sandra E Nicholson.
Cancers (Basel), 2020 Apr 16; 12(4). PMID: 32290478    Free PMC article.
Review.
Checkpoint Inhibitors and Engineered Cells: New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies.
Massimo Giuliani, Alessandro Poggi.
Cells, 2020 Jul 03; 9(7). PMID: 32610578    Free PMC article.
Review.
Harnessing NK Cell Checkpoint-Modulating Immunotherapies.
Sachin Kumar Singh Chauhan, Ulrike Koehl, Stephan Kloess.
Cancers (Basel), 2020 Jul 10; 12(7). PMID: 32640575    Free PMC article.
Review.
Targeting immune checkpoints in hematological malignancies.
Basit Salik, Mark J Smyth, Kyohei Nakamura.
J Hematol Oncol, 2020 Aug 14; 13(1). PMID: 32787882    Free PMC article.
Review.
Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects.
Barbara Bassani, Denisa Baci, +3 authors, Lorenzo Mortara.
Cancers (Basel), 2019 Apr 04; 11(4). PMID: 30939820    Free PMC article.
Review.
NK-mediated antibody-dependent cell-mediated cytotoxicity in solid tumors: biological evidence and clinical perspectives.
Cristiana Lo Nigro, Marco Macagno, +3 authors, Marco Carlo Merlano.
Ann Transl Med, 2019 Apr 26; 7(5). PMID: 31019955    Free PMC article.
Review.
Strategies to Augment Natural Killer (NK) Cell Activity against Solid Tumors.
Ziqing Chen, Ying Yang, Lisa L Liu, Andreas Lundqvist.
Cancers (Basel), 2019 Jul 26; 11(7). PMID: 31340613    Free PMC article.
Review.
Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells.
Monika Holubova, Martin Leba, +3 authors, Daniel Lysak.
Int J Mol Sci, 2019 Jul 18; 20(14). PMID: 31311121    Free PMC article.
Natural killer cell-based immunotherapy for acute myeloid leukemia.
Jing Xu, Ting Niu.
J Hematol Oncol, 2020 Dec 09; 13(1). PMID: 33287858    Free PMC article.
Review.
NK cells for cancer immunotherapy.
Noriko Shimasaki, Amit Jain, Dario Campana.
Nat Rev Drug Discov, 2020 Jan 08; 19(3). PMID: 31907401
Review.
TRIGGERED: could refocused cell signaling be key to natural killer cell-based HIV immunotherapeutics?
Sho Sugawara, Cordelia Manickam, R Keith Reeves.
AIDS, 2020 Oct 30; 35(2). PMID: 33116071    Free PMC article.
Review.
Exploring the NK cell platform for cancer immunotherapy.
Jacob A Myers, Jeffrey S Miller.
Nat Rev Clin Oncol, 2020 Sep 17; 18(2). PMID: 32934330    Free PMC article.
Review.
Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors.
Nayoung Kim, Dong-Hee Lee, +5 authors, Hun Sik Kim.
BMB Rep, 2020 Dec 11; 54(1). PMID: 33298244    Free PMC article.
Review.
Update of early phase clinical trials in cancer immunotherapy.
Dae Ho Lee.
BMB Rep, 2021 Jan 08; 54(1). PMID: 33407992    Free PMC article.
Review.
Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy.
Martina Molgora, Victor S Cortez, Marco Colonna.
Cancers (Basel), 2021 Feb 07; 13(4). PMID: 33546248    Free PMC article.
Review.
Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future.
Margaret G Lamb, Hemalatha G Rangarajan, Brian P Tullius, Dean A Lee.
Stem Cell Res Ther, 2021 Mar 27; 12(1). PMID: 33766099    Free PMC article.
Review.
The Advances and Challenges of NK Cell-Based Cancer Immunotherapy.
Synat Kang, Xuefeng Gao, +3 authors, Li Yu.
Curr Oncol, 2021 Mar 04; 28(2). PMID: 33652996    Free PMC article.
Review.
Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy.
Rasa Islam, Aleta Pupovac, +4 authors, Alan Trounson.
Cells, 2021 May 06; 10(5). PMID: 33946954    Free PMC article.
Review.
Fc-engineered anti-CD33 monoclonal antibody potentiates cytotoxicity of membrane-bound interleukin-21 expanded natural killer cells in acute myeloid leukemia.
Rajeswaran Mani, Girish Rajgolikar, +7 authors, Sumithira Vasu.
Cytotherapy, 2020 Apr 19; 22(7). PMID: 32303428    Free PMC article.
The "Magic Bullet" Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era.
Nina Miazek-Zapala, Aleksander Slusarczyk, +4 authors, Malgorzata Bobrowicz.
Cells, 2021 Jul 03; 10(6). PMID: 34203935    Free PMC article.
Review.
Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment.
Natasha Mupeta Kaweme, Fuling Zhou.
Front Immunol, 2021 Jul 06; 12. PMID: 34220833    Free PMC article.
Review.
Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives.
Nicolas Jacquelot, Cyril Seillet, +3 authors, Pamela S Ohashi.
Int J Mol Sci, 2021 Aug 28; 22(16). PMID: 34445750    Free PMC article.
Review.
The Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors.
Rodion A Velichinskii, Maria A Streltsova, +2 authors, Elena I Kovalenko.
Int J Mol Sci, 2021 Nov 14; 22(21). PMID: 34768814    Free PMC article.
Review.
Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges.
Alessandro Poggi, Maria Raffaella Zocchi.
Mol Ther Oncolytics, 2022 Jan 04; 24. PMID: 34977340    Free PMC article.
Review.
Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors.
Guangyu Lian, Thomas Shiu-Kwong Mak, Xueqing Yu, Hui-Yao Lan.
Int J Mol Sci, 2022 Jan 12; 23(1). PMID: 35008589    Free PMC article.
Review.
Natural Killer Cell-Mediated Immunotherapy for Leukemia.
Michaela Allison, Joel Mathews, Taylor Gilliland, Stephen O Mathew.
Cancers (Basel), 2022 Feb 16; 14(3). PMID: 35159109    Free PMC article.
Review.
Lirilumab and Avelumab Enhance Anti-HPV+ Cervical Cancer Activity of Natural Killer Cells via Vav1-Dependent NF-κB Disinhibition.
Hongli Liu, Sihui Zhou, +7 authors, Nan Wu.
Front Oncol, 2022 Feb 18; 12. PMID: 35174079    Free PMC article.
Blockade of inhibitory killer cell immunoglobulin-like receptors and IL-2 triggering reverses the functional hypoactivity of tumor-derived NK-cells in glioblastomas.
Cüneyt Sönmez, Johannes Wölfer, +6 authors, Oliver M Grauer.
Sci Rep, 2022 Apr 28; 12(1). PMID: 35474089    Free PMC article.
Natural killer cells: a promising immunotherapy for cancer.
Junfeng Chu, Fengcai Gao, +4 authors, Yanyan Liu.
J Transl Med, 2022 May 24; 20(1). PMID: 35606854
Review.
Natural killer cells and acute myeloid leukemia: promises and challenges.
Shayan Rahmani, Niloufar Yazdanpanah, Nima Rezaei.
Cancer Immunol Immunother, 2022 Jun 01;. PMID: 35639116
Review.