Background
Achieving ART-free control of HIV is a global priority. N-803, an IL-15 superagonist, expands and activates CD8 T and NK cells and, in rhesus macaques, induced post-ART viral control when combined with bNAbs. A5386 is an open-label phase 1 trial evaluating safety and virologic effects of N-803 (q3wk x8) +/- single infusions of bNAbs (10-1074-LS+VRC07-523LS) in adults with chronic ART-treated HIV.
Methods
Participants in the N-803+bNAb arm had susceptibility to ≥1bNAb (10-1074: IC90≤1.5 µg/mL and MPI ≥98%; VRC07-523LS: IC80≤1µg/mL). At wk52, ART was interrupted (ATI) with close monitoring. The primary endpoint—plasma HIV RNA <200 cp, at ATI wk8—is presented for the N-803+bNAb arm, along with intact HIV DNA (q4ddPCR) and T cell phenotyping. Safety and tolerability outcomes are presented for both arms; ATIs remain ongoing for the N-803-alone arm.
Results
Of 118 screened, 23 enrolled in the N-803+bNAbs arm and 25 in the N-803 arm; 90% male, 19% Hispanic, 40% non-white, median age 50y. In the N-803+bNAbs arm, 91% were susceptible to VRC07-523LS and 48% to 10-1074-LS. All 23 completed bNAb treatment, 2 with grade 2 AEs; 33/48 across both arms completed all N-803 doses, 10 completed 5-7 doses. N-803-related grade 1-2 ISR or systemic AEs were seen in nearly all participants; Grade ≥3 AEs related to N-803 occurred (17%, 8/48). Nineteen N-803+bNAbs participants entered the ATI: 1 (5%) had HIV RNA <200 cpm at ATI wk8, 3 (16%) had HIV RNA <1000 cpm at ATI wk8, 2 remained off ART for 24 wks with 1 in long term ATI follow-up (see Figure). In a subset (n=7) 46 wks after dosing, geometric mean concentration [95% CI] of VRC07-523LS was 2.1 [1.2-3.9] µg/mL (n=7, 5 quantifiable) and 10-1074-LS was 7.5 [5.3-10.6] µg/mL (n=7). Among N-803+bNAb participants (n=20), intact HIV DNA (q4ddPCR) decreased by median 0.24 log10 cps/106 CD4 T-cells after 5 N-803 doses (IQR 0.004–0.43 log10; p=0.02), with return towards baseline 8wks after dosing. Increases in stem-cell memory CD8 T cells (1.31-fold; IQR 0.84–1.59; p=0.04), a reduction in TOX⁺PD-1⁺ CD8 T cells (0.81-fold; IQR 0.64–0.97; p=0.002) and trend towards increased TCF-1 (p=0.10) were observed.
Conclusions
N-803+dual bNAbs was generally tolerated and associated with reductions in intact proviruses and CD8 T cell phenotype shifts previously associated with virologic control. While the frequency of ART-free viral suppression did not meet the primary endpoint, ongoing analyses will investigate immunologic and virologic effects in relation to post-ATI outcomes.
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