IL-15 Superagonist + Antibodies for HIV/AIDS

Recruiting at 17 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Integrase inhibitors, NRTIs

Must not be taking: Immunomodulatory medications

Disqualifiers: AIDS, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 52 weeks

118 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with HIV-1. Researchers aim to determine if N-803, an IL-15 superagonist (a type of immune system booster), alone or with specific antibodies, can control the virus during breaks from usual HIV treatment. The trial seeks participants who have been on antiretroviral therapy (ART) for at least 96 weeks, with stable HIV levels and a specific ART regimen. Those managing HIV well with ART and meeting these criteria might find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires participants to be on a specific ART regimen with an integrase inhibitor and two NRTIs or dolutegravir/lamivudine. If you are on a different ART regimen, you may need to change your medications to meet this requirement.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found N-803 to be safe and well-tolerated in people living with HIV, with no major safety issues reported. Research suggests that N-803 might help reduce the virus in patients on antiretroviral therapy (ART). Another study showed that N-803, when combined with natural killer cells (immune cells that fight infections), could potentially lower the amount of virus in the body.

For the combination treatment with N-803, 10-1074, and VRC07-523LS (special antibodies that target HIV), less specific data is available. However, these antibodies have been tested in other studies and are generally considered safe in similar situations. Overall, early findings suggest that the treatments tested in this trial are safe for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about N-803 for HIV/AIDS because it offers a novel approach compared to current antiretroviral therapies that primarily suppress the virus. N-803 acts as an IL-15 superagonist, which can potentially enhance the immune system by activating natural killer (NK) cells and T-cells to target and eliminate HIV-infected cells. Additionally, in combination with the antibodies 10-1074 and VRC07-523LS, it may provide a synergistic effect, offering a promising strategy to reduce the viral reservoir and improve immune response. Unlike standard treatments that focus on controlling the virus, N-803 aims to empower the body's immune system to eradicate it, introducing a new frontier in HIV treatment possibilities.

What evidence suggests that this trial's treatments could be effective for HIV/AIDS?

Research has shown that N-803, a special type of medicine, may help control HIV by boosting the activity of natural killer (NK) cells. These cells, part of the immune system, can destroy cells infected with HIV. Studies suggest that N-803 can reduce the amount of hidden virus in people taking antiretroviral therapy (ART). In this trial, participants in Arm A will receive N-803 alone, while participants in Arm B will receive N-803 combined with certain antibodies, such as 10-1074 and VRC07-523LS. Animal studies with these antibodies have shown promise in keeping the virus under control for a long time. Therefore, using N-803 with these antibodies could potentially improve HIV treatment outcomes. ^{1 2 3 5 6}

Who Is on the Research Team?

Timothy Wilkin, MD, MPH

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for adults with HIV/AIDS who've been on ART including an integrase inhibitor and NRTIs or dolutegravir/lamivudine for at least 96 weeks, have a stable CD4 count, no history of AIDS-defining illness except recurrent pneumonia, and agree to use contraception. They must not be pregnant, breastfeeding, or have used immunomodulatory meds recently.

Inclusion Criteria

I am infected with HIV-1.

Select laboratory results within 90 days of randomization

CD4 cell count nadir ≥200 cells/mm^3

Exclusion Criteria

I have a history of heart disease.

I am currently on HIV treatment that is not NRTI or integrase inhibitor.

Breastfeeding or pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 12 weeks

1 visit (in-person)

Treatment

Participants receive N-803 with or without combination bNAbs for HIV-1 control

52 weeks

Multiple visits (in-person) every 3 weeks

Analytic Treatment Interruption (ATI)

Participants interrupt antiretroviral therapy and are monitored closely

Up to 24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 10-1074
• N-803
• VRC07-523LS

Trial Overview The study tests the safety and effectiveness of N-803 (an IL-15 superagonist) alone or combined with bNAbs (VRC07-523LS & 10-1074) in controlling HIV without regular treatment. Participants will temporarily stop their usual ART to see if these new drugs can maintain low HIV levels.

How Is the Trial Designed?

Group I: Arm B: N-803 in combination with 10-1074 and VRC07-523LS Experimental Treatment 3 Interventions

Participants will receive N-803 in combination with 10-1074 and VRC07-523LS as follows: * At Step 2 entry: * VRC07-523LS 20 mg/kg * 10-1074 30 mg/kg * At Step 2, week 1: N-803 6 mcg/kg every 3 weeks for eight doses * At Step 2, week 9: 10-1074 30 mg/kg

Group II: Arm A: N-803 only Experimental Treatment 1 Intervention

Participants will receive N-803 6 mcg/kg 1 week after Step 2 entry and then every 3 weeks for a total of eight doses.

N-803 is already approved in United States for the following indications:

Approved in United States as N-803 for:

• Non-muscle invasive bladder cancer (NMIBC) in combination with BCG

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Rockefeller University

Collaborator

Trials

162

Recruited

16,700+

ImmunityBio, Inc.

Industry Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

The phase 1 study of N-803, an IL-15 superagonist, demonstrated that it is safe and well-tolerated in 16 ART-suppressed individuals living with HIV, with the maximum tolerated dose identified as 6.0 mcg kg-1.

N-803 treatment led to increased activation of immune cells and a significant decrease in the frequency of cells with inducible HIV provirus, suggesting potential for reducing HIV reservoirs, although further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: a phase 1 trial. Miller, JS., Davis, ZB., Helgeson, E., et al.[2022]

The combination of N-803, an IL15 receptor superagonist, with rituximab was found to be safe and well tolerated in patients with relapsed/refractory non-Hodgkin lymphoma, leading to durable clinical responses even in those resistant to rituximab.

N-803 significantly enhanced the activation and expansion of natural killer (NK) cells and CD8+ T cells, indicating its potential to improve the effectiveness of tumor-targeting monoclonal antibodies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma. Foltz, JA., Hess, BT., Bachanova, V., et al.[2022]

IL-15 superagonists, created by combining IL-15 with its receptor, show enhanced efficacy in stimulating natural killer (NK) and CD8+ T cells, which are crucial for fighting cancer, and have demonstrated tumor regression in animal studies.

Currently, there are fourteen ongoing phase I/II clinical trials investigating the safety and efficacy of IL-15 superagonists in cancer patients, with results on toxicity and effectiveness eagerly anticipated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent. Guo, Y., Luan, L., Patil, NK., et al.[2018]

Treatment with an IL-15 superagonist significantly enhances the anti-HIV activity of natural killer (NK) cells, leading to a potent suppression of acute HIV-1 infection in humanized mice, even when administered three days post-infection.

The effectiveness of the IL-15 superagonist in inhibiting HIV-1 infection relies on the presence of NK cells, as their removal completely negated the treatment's benefits, highlighting the critical role of activated NK cells in this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice. Seay, K., Church, C., Zheng, JH., et al.[2018]

ALT-803, an interleukin-15 superagonist, can boost the immune response by increasing CD8+ T and NK cell populations in SIV-positive rhesus macaques, leading to a temporary reduction in viral loads by about 2 logs during treatment cycles.

The study highlights that while ALT-803 shows promise as an immunomodulatory agent for controlling HIV/SIV replication, the effects are transient due to decreased T cell responsiveness and increased immunosuppressive T cells over time, suggesting the need for optimized treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALT-803 Transiently Reduces Simian Immunodeficiency Virus Replication in the Absence of Antiretroviral Treatment. Ellis-Connell, AL., Balgeman, AJ., Zarbock, KR., et al.[2020]

N-803 enhances the immune response by increasing the function of CD8 T cells and NK cells, leading to a transient decline in plasma viremia in SIV+ rhesus macaques, particularly in those with low viral loads.

The effectiveness of N-803 is greater in SIV+ animals that can naturally control the virus, as it boosts the proliferation and killing capacity of SIV-specific immune cells more significantly in these 'controllers' compared to 'noncontrollers'.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Control of Simian Immunodeficiency Virus Infection in Prophylactically Vaccinated, Antiretroviral Treatment-Naive Macaques Is Required for the Most Efficacious CD8 T Cell Response during Treatment with the Interleukin-15 Superagonist N-803. Ellis-Connell, AL., Balgeman, AJ., Harwood, OE., et al.[2023]

IL-15 is a crucial cytokine that enhances T cell and NK cell responses against HIV/SIV, but its use can sometimes lead to unwanted immune activation and faster disease progression, highlighting the need for careful timing in treatment.

The IL-15 superagonist N-803 shows promise in improving immune responses against HIV/SIV by enhancing CD8+ T cell activity and potentially reversing viral latency, making it a valuable candidate for combination therapies with antiretroviral treatments and vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Potential of IL-15 and N-803 in HIV/SIV Infection. Harwood, O., O'Connor, S.[2022]

Citations

1. insight.jci.org insight.jci.org/articles/view/190831

Impact of the IL-15 superagonist N-803 on lymphatic ... Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10537516/

IL-15 and N-803 for HIV Cure Approaches - PMC Similarly, IL-15 treatment of NK cells results in enhanced cytotoxicity [77,84,85,86], killing capacity of HIV-infected cells [79,84,85,87,88], production of ...

3. immunitybio.com immunitybio.com/n-803-combined-with-natural-killer-cells-showed-potential-to-reduce-hiv-viral-load-in-hiv-positive-subjects-part-of-hiv-cure-study/

HIV Cure Study: N-803 with Natural Killer Cells May ... Data from a Phase 1 pilot study showed N-803 combined with natural killer cells could have the potential to reduce viral load in people living with HIV.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04340596

Safety, Tolerability, and Efficacy of IL-15 Superagonist (N- ... This study will evaluate the safety, tolerability, and efficacy of N-803, an IL-15 superagonist, with or without combination broadly neutralizing antibodies ...

5. astctjournal.org astctjournal.org/article/S2666-6367(24)00691-2/fulltext

N-803, an IL-15 Superagonist Complex as Maintenance ... A Phase 2 trial of N-803 as maintenance after allogeneic transplant for AML/MDS showed that relapse decreased with more than 3 doses of N-803.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35102335/

Safety and virologic impact of the IL-15 superagonist N-803 ... 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 ...