bNAbs and Anti-PD-1 in HIV

A vizsgálat adatai

Ki végzi

Ole Schmeltz Søgaard

Azonosító

NCT07820813EU 2025-523725-17-00

A regiszteradat frissítve

2026. szeptember 15.

Eredeti leírás

Antiretroviral therapy (ART) has significantly extended the life expectancy of people living with HIV-1 (PLWH), but it does not cure the infection. Broadly neutralizing antibodies (bNAbs), such as 3BNC117 and 10-1074, not only neutralize circulating virus but also engage the immune system to enhance HIV-1-specific CD8+ T cell responses and stimulate autologous neutralizing antibody production. In some individuals who discontinue ART, bNAb treatment resulted in long-term post-treatment control. However, a major obstacle to immunotherapeutic strategies in PLWH is the immune dysfunction that persists despite long-term suppressive ART. One contributing factor is the immune checkpoint receptor programmed death-1 (PD-1), which is expressed on T cells and suppresses their function when engaged by its ligands. Blocking PD-1 with monoclonal antibodies (mAbs) can reverse T cell exhaustion, a strategy that has resulted in extraordinary increases in survival and cure in cancer treatment and in ex vivo and animal studies of HIV. These findings support the rationale for incorporating PD-1 inhibition in HIV cure strategies. Low-dose nivolumab, an anti-PD-1 mAb, has been shown to be safe in clinical trials. The hypothesis is that combining a single low-dose of nivolumab with long-acting bNAbs (3BNC117-LS and 10-1074-LS) during an analytical treatment interruption (ATI) will reduce T cell exhaustion and boost HIV-1-specific immune responses, as a novel strategy to induce sustained virological control without ART even after the bNAbs have been cleared from the body.A teljes eredeti leírásKevesebb

Inducing Durable Immunological Control of HIV-1 Through Administration of Long-acting Broadly Neutralizing Antibodies and Low-dose Anti-PD-1 - a Randomized, Double-blinded, Placebocontrolled Trial (the IDUNN Trial)

Antiretroviral therapy (ART) has significantly extended the life expectancy of people living with HIV-1 (PLWH), but it does not cure the infection. Broadly neutralizing antibodies (bNAbs), such as 3BNC117 and 10-1074, not only neutralize circulating virus but also engage the immune system to enhance HIV-1-specific CD8+ T cell responses and stimulate autologous neutralizing antibody production. In some individuals who discontinue ART, bNAb treatment resulted in long-term post-treatment control. However, a major obstacle to immunotherapeutic strategies in PLWH is the immune dysfunction that persists despite long-term suppressive ART. One contributing factor is the immune checkpoint receptor programmed death-1 (PD-1), which is expressed on T cells and suppresses their function when engaged by its ligands. Blocking PD-1 with monoclonal antibodies (mAbs) can reverse T cell exhaustion, a strategy that has resulted in extraordinary increases in survival and cure in cancer treatment and in ex vivo and animal studies of HIV. These findings support the rationale for incorporating PD-1 inhibition in HIV cure strategies. Low-dose nivolumab, an anti-PD-1 mAb, has been shown to be safe in clinical trials. The hypothesis is that combining a single low-dose of nivolumab with long-acting bNAbs (3BNC117-LS and 10-1074-LS) during an analytical treatment interruption (ATI) will reduce T cell exhaustion and boost HIV-1-specific immune responses, as a novel strategy to induce sustained virological control without ART even after the bNAbs have been cleared from the body.

Bevonási feltételek: Ability and willingness to provide informed consent; HBV sAg or HBV DNA as well as HCV Ag or HCV RNA negative or anti-core antibody negative; Current CD4 count >500 cells/μL (at screening); Plasma HIV-1 RNA <50 copies/mL by standard assays for at least 15 months (a single measurement >50 but <500 copies/mL during this time period is allowable); On integrase inhibitor (INSTI) or boosted protease inhibitor (PI) based regimen at time of randomization, if previously on non-nucleoside reverse transcriptase inhibitor (NNRTI) has switched at least 4 weeks prior to randomization; Females of childbearing potential (i.e., participants who have not been postmenopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy), negative serum or urine pregnancy test monthly; Pregnancy prevention (heterosexual contact(s)):; o Females must agree to use highly eWective contraceptive methods: Hormonal contraception, intrauterine device, or intrauterine hormone-releasing system from at least 2 weeks before the bNAb infusion and for entire trial period of 60 weeks and 15 months following the bNAb infusion; Transmission prevention; Participants must agree to use barrier prevention during ART interruption and until plasma HIV-1 RNA levels are resuppressed again following ART re-start; Partners of study participants should be willing to receive counselling on the need for PrEP according to national recommendations.

Kizáró feltételek: Solid organ transplant; Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to screening; TPO antibodies >35 IU/mL; Any vaccination 2 weeks prior to baseline; Any significant acute infection (e.g. influenza, COVID-19) or any other clinically significant illness 2 weeks prior to screening; Have received a long-acting ART regimen within the last 12 months (e.g. cabotegravir or lenacaprivir containing regimen); Current, or history of:; Malignancy, excluding non-melanoma skin cancers; Autoimmune or antibody-mediated diseases (including not limited to type 1 diabetes mellitus, inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insuWiciency, hypothyroidism and/or hyperthyroidism, autoimmune thyroiditis, sarcoidosis, and vitiligo); Known hypersensitivity to the components of 3BNC117-LS, 10-1074-LS or nivolumab or their analogues; HIV-1 reservoir predicted resistant to neutralization by 10-1074 using genotypic analysis (as defined in section 11.3.2.9); Known HIV-1 subtype CRF01-AE due to resistance to 10-1074-LS; Any other conditions, which in the opinion of the investigator would make the participant unsuitable for inclusion, or could interfere with the participants participating in or completion of the study; Clinically significant cardiovascular disease (e.g., cardiac insuWiciency, coronary artery disease, cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, family history of sudden death); Laboratory abnormalities in the parameters listed below:; Estimated glomerular filtration rate (eGFR) <60 mL/min; AST or ALT >x1.25 upper limit of normal (ULN); Partial thromboplastin time >1.25 ULN; Positive Quantiferon test; Pregnancy or lactation; Known resistance to >2 classes of ART; Participation in other interventional trial.

ClinicalTrials.gov NCT07820813 · EU CTIS 2025-523725-17-00