PMID- 35102335
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20220506
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 28
IP  - 2
DP  - 2022 Feb
TI  - Safety and virologic impact of the IL-15 superagonist N-803 in people living with 
      HIV: a phase 1 trial.
PG  - 392-400
LID - 10.1038/s41591-021-01651-9 [doi]
AB  - There is no cure for HIV infection, and lifelong antiretroviral therapy (ART) is 
      required. N-803 is an IL-15 superagonist comprised of an N72D mutant IL-15 
      molecule attached to its alpha receptor and a human IgG1 fragment designed to 
      increase IL-15 activity. Preclinical studies with both HIV and SIV suggest that 
      the drug has potential to reduce virus reservoirs by activating virus from 
      latency and enhancing effector function. We conducted a phase 1 study of N-803 ( 
      NCT02191098 ) in people living with HIV, the primary objective of which was to 
      assess the safety and tolerability of the drug, with an exploratory objective of 
      assessing the impact on peripheral virus reservoirs. ART-suppressed individuals 
      were enrolled into a dose-escalation study of N-803 in four different cohorts 
      (0.3, 1.0, 3.0 and 6.0 mcg kg(-1)). Each cohort received three doses total, 
      separated by at least 1 week. We enrolled 16 individuals, of whom 11 completed 
      all three doses. The maximum tolerated dose was 6.0 mcg kg(-1). The primary 
      clinical adverse events (AEs) reported were injection site rash and adenopathy, 
      and four participants experienced a grade 1 or grade 2 QTc prolongation. No 
      significant laboratory AEs attributable to N-803 were observed. In exploratory 
      analyses, N-803 was associated with proliferation and/or activation of CD4(+) and 
      CD8(+) T cells and natural killer cells that peaked at 4 d after dosing. IFN-gamma, 
      IP-10, MCP-1 and IL-15 increased during treatment. HIV transcription in memory 
      CD4 T cells and intact proviral DNA initially increased after N-803 treatment; 
      however, there was a small but significant decrease in the frequency of 
      peripheral blood mononuclear cells with an inducible HIV provirus that persisted 
      for up to 6 months after therapy. These data suggest that N-803 administration in 
      ART-suppressed people living with HIV is safe and that larger clinical trials are 
      needed to further investigate the effects of N-803 on HIV reservoirs.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
FAU - Miller, Jeffrey S
AU  - Miller JS
AUID- ORCID: 0000-0002-0339-4944
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Davis, Zachary B
AU  - Davis ZB
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Helgeson, Erika
AU  - Helgeson E
AD  - Division of Biostatistics, University of Minnesota School of Public Health, 
      Minneapolis, MN, USA.
FAU - Reilly, Cavan
AU  - Reilly C
AD  - Division of Biostatistics, University of Minnesota School of Public Health, 
      Minneapolis, MN, USA.
FAU - Thorkelson, Ann
AU  - Thorkelson A
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Anderson, Jodi
AU  - Anderson J
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Lima, Noemia S
AU  - Lima NS
AUID- ORCID: 0000-0003-4399-487X
AD  - Human Immunology Section, Vaccine Research Center, National Institute of Allergy 
      and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Jorstad, Siri
AU  - Jorstad S
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Hart, Geoffrey T
AU  - Hart GT
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
FAU - Lee, John H
AU  - Lee JH
AD  - ImmunityBio, Culver City, CA, USA.
FAU - Safrit, Jeffrey T
AU  - Safrit JT
AD  - ImmunityBio, Culver City, CA, USA.
FAU - Wong, Hing
AU  - Wong H
AD  - HCW Biologics, Miramar, FL, USA.
AD  - HCW Biologics but was with Altor BioSciences at the start of the study, Miramar 
      FL, USA.
FAU - Cooley, Sarah
AU  - Cooley S
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA.
AD  - Fate Therapeutics, San Diego, CA, USA.
FAU - Gharu, Lavina
AU  - Gharu L
AD  - Human Immunology Section, Vaccine Research Center, National Institute of Allergy 
      and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Chung, Hyunsoo
AU  - Chung H
AUID- ORCID: 0000-0002-8192-8358
AD  - Human Immunology Section, Vaccine Research Center, National Institute of Allergy 
      and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Soon-Shiong, Patrick
AU  - Soon-Shiong P
AUID- ORCID: 0000-0002-4682-8298
AD  - ImmunityBio, Culver City, CA, USA.
FAU - Dobrowolski, Curtis
AU  - Dobrowolski C
AD  - Department of Molecular Biology and Microbiology, Medical School, Case Western 
      Reserve University, Cleveland, OH, USA.
AD  - Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of 
      Technology and Emory School of Medicine, Atlanta, GA, USA.
FAU - Fletcher, Courtney V
AU  - Fletcher CV
AUID- ORCID: 0000-0002-3703-7849
AD  - Antiviral Pharmacology Laboratory, UNMC Center for Drug Discovery, University of 
      Nebraska Medical Center, Omaha, NE, USA.
FAU - Karn, Jonathan
AU  - Karn J
AD  - Department of Molecular Biology and Microbiology, Medical School, Case Western 
      Reserve University, Cleveland, OH, USA.
FAU - Douek, Daniel C
AU  - Douek DC
AD  - Human Immunology Section, Vaccine Research Center, National Institute of Allergy 
      and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Schacker, Timothy W
AU  - Schacker TW
AUID- ORCID: 0000-0002-2451-9937
AD  - Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 
      USA. schacker@umn.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT02191098
GR  - U24 AI143502/AI/NIAID NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220131
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (ALT-803)
RN  - 0 (Interleukin-15)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
MH  - CD4-Positive T-Lymphocytes
MH  - CD8-Positive T-Lymphocytes
MH  - *HIV Infections/drug therapy
MH  - *HIV-1
MH  - Humans
MH  - Interleukin-15/genetics
MH  - Leukocytes, Mononuclear
MH  - Recombinant Fusion Proteins
MH  - Viral Load
EDAT- 2022/02/02 06:00
MHDA- 2022/04/27 06:00
CRDT- 2022/02/01 06:09
PHST- 2020/08/28 00:00 [received]
PHST- 2021/11/30 00:00 [accepted]
PHST- 2022/02/02 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
PHST- 2022/02/01 06:09 [entrez]
AID - 10.1038/s41591-021-01651-9 [pii]
AID - 10.1038/s41591-021-01651-9 [doi]
PST - ppublish
SO  - Nat Med. 2022 Feb;28(2):392-400. doi: 10.1038/s41591-021-01651-9. Epub 2022 Jan 
      31.