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Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: a phase 1 trial

Nature Medicine volume 28, pages 392–400 (2022)Cite this article

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Abstract

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-γ, 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.

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Fig. 1: Pharmacokinetic analysis of changes in IL-15 after third dose of N-803.
Fig. 2: Characterization of NK and T cell responses to N-803.
Fig. 3: Change in absolute number of NK, CD4, and CD8 T cells with N-803.
Fig. 4: Virologic assessments of the impact of N-803 on the inducible reservoir in the 11 participants who received all three doses of N-803.

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Data availability

The datasets generated and/or analyzed in this study are attached. Any additional data are available from the corresponding author. All data are de-identified, and no participant-identifiable information will be disclosed. Source data are provided with this paper.

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Acknowledgements

This research was funded entirely by a grant from Altor BioSciences and ImmunityBio to T.W.S. and by NIH U24AI143502 to Accelevir to help support the IPDA analyses. Neither Altor BioSciences nor ImmunityBio played any role in study design or execution of the study. P.S.-S. and J.L. are affiliated with ImmunityBio, and H.W. was CEO of Altor BioSciences when the study was initiated. We would like to thank E. Jeng for assistance with setting up the trial and A. T. Haase for insight and assistance in the analysis of data.

Author information

Author notes

  1. Hing Wong

    Present address: HCW Biologics but was with Altor BioSciences at the start of the study, Miramar FL, USA

  2. Sarah Cooley

    Present address: Fate Therapeutics, San Diego, CA, USA

  3. Curtis Dobrowolski

    Present address: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA

Authors and Affiliations

  1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA

    Jeffrey S. Miller, Zachary B. Davis, Ann Thorkelson, Jodi Anderson, Siri Jorstad, Geoffrey T. Hart, Sarah Cooley & Timothy W. Schacker

  2. Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN, USA

    Erika Helgeson & Cavan Reilly

  3. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Noemia S. Lima, Lavina Gharu, Hyunsoo Chung & Daniel C. Douek

  4. ImmunityBio, Culver City, CA, USA

    John H. Lee, Jeffrey T. Safrit & Patrick Soon-Shiong

  5. HCW Biologics, Miramar, FL, USA

    Hing Wong

  6. Department of Molecular Biology and Microbiology, Medical School, Case Western Reserve University, Cleveland, OH, USA

    Curtis Dobrowolski & Jonathan Karn

  7. Antiviral Pharmacology Laboratory, UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, USA

    Courtney V. Fletcher

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Contributions

All authors made substantial contributions to this work. J.S.M. and T.W.S. designed the clinical protocol and provided oversight for the conduct of the trial. Z.B.D., J.A., N.S.L., L.G., H.C., C.D., J.K., C.V.M. and D.C.D. provided data analyses. J.H.L., J.T.S., H.W. and P.S.-S. provided access to N-803 and provided financial resources to pay for the study. E.H. and C.R. provided statistical support and analysis. A.T., S.J., T.W.S. and J.S.M. contributed to identifying participants and following them through the clinical protocol. J.S.M., C.V.F., J.K., D.C.D. and T.W.S. prepared the manuscript.

Corresponding author

Correspondence to Timothy W. Schacker.

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Competing interests

H.W., J.T.S., J.H.L. and P.S.-S. are affiliated with Altor BioSciences (H.W.) or ImmunityBio (J.T.S., J.H.L. and P.S.-S.), which provided N-803 and paid for the trial. None of these authors had any influence on study design or data interpretation. There are no other competing interests to report.

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Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Editor recognition statement: Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Dose related increases in IL-15 in plasma.

Plasma levels of IL-15 obtained just prior to the first dose and then at several time-points over the subsequent 24 hours and at Day 4 are plotted for each dose. We plotted the 3 participants at each dose that completed all 3 doses. We noted that 2 individuals at the 1 mcg/kg dose (A) had high baseline levels of IL-15 whereas all 6 individuals at the 3 and 6 mcg/kg dose had low baseline levels and the expected increase with each subsequent injection.

Source data

Extended Data Fig. 2 Changes in inflammatory cytokines after administration of N-803.

There is a significant increase in IP10, MCP-1 (p = 0.005, 0.036, respectively by permutation tests), and a non-significant increase in IFNγ (p = 0.08) with administration of N-803. Data are presented as the mean and SEM derived from the 9 individuals who completed the 1.0 (N = 3), 3.0 (N = 3), and 6.0 (N = 3) mcg/kg dosing scheme.

Source data

Extended Data Fig. 3

Flow cytometry gating strategy.

Extended Data Fig. 4 Cell viability and cytokine release after stimulation.

IL-2, IFNg, and TNF expression is measured in CD4 T cells (a) and CD8 T cells (b) after stimulation in a subset of 5 individuals where there were sufficient samples for analysis. There was no consistent change in IFNγ, IL-2, or TNF expression in either cell type. Cell viability is also presented (c).

Source data

Extended Data Fig. 5 Proportion of participants with detectable HIV RNA in plasma after each dose.

We measured plasma viral load (pVL) pre-dose 1 and again at 8, 12, and 24 hours after each dose and again at day 4. At the pre-dose 1 measure, only 1/11 (9.1%) had a detectable pVL (<20 copies/ml) and of the 132 samples obtained during follow-up, 30 (22.7%) had detectable HIV RNA in 10/11 (91%) participants. Of the positive measurements, 3 were greater than 20 copies/ml (23, 30, 35 copies/ml) and the remaining were reported as HIV RNA detected but < 20 copies/ml. These data are consistent with small transient increases in HIV transcription in the peripheral blood compartment associated with N-803 administration.

Source data

Supplementary information

Supplementary Information

Supplementary tables and clinical protocol

Reporting Summary

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Miller, J.S., Davis, Z.B., Helgeson, E. et al. Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: a phase 1 trial. Nat Med 28, 392–400 (2022). https://doi.org/10.1038/s41591-021-01651-9

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