CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

426

Unadjuvanted CD40.HIVRI.ENV Vaccine Late Boost Induces Durable Immune Responses: ANRS/VRI06 Trial Lucile Hardel 1 , Christiane Moog 1 , Aurélie Wiedemann 1 , Mélany Durand 1 , Odile Launay 2 , Fabio Candotti 3 , Véronique Rieux 1 , Yves Lévy 4 , Alpha Diallo 1 , Song Ding 5 , Mireille Centlivre 4 , Rodolphe Thiebaut 6 , Giuseppe Pantaleo 3 , Jean-Daniel Lelièvre 7 , Laura Richert 6 1 French National Institute of Health and Medical Research (Inserm), Paris, France, 2 Cochin Hospital, Paris, France, 3 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 4 Vaccine Research Institute, Créteil, France, 5 EuroVacc Foundation, Amsterdam, Netherlands, 6 University of Bordeaux, Bordeaux, France, 7 Hôpital Henri Mondor, Créteil, France Background: CD40.HIVRI.Env is a gp140 Env (Clade C 96ZM65) fused to an anti-CD40 mAb to target CD40-expressing dendritic cells. The ANRS/VRI06 phase I trial (NCT04842682) enrolled 72 non HIV-infected volunteers to receive either 0.3, 1.0, or 3.0 mg of CD40.HIVRI.Env (TLR3-Hiltonol® adjuvanted) alone or co-administered with DNA-HIV-PT123 at weeks (W) 0, 4 and 24, randomized 5:1 active vs. placebo. Results showed good safety and strong immunogenicity of vaccines until W48 regardless dose or combination ( Y. Levy et al., eClinicalMedicine, in press ). Methods: Beyond W48 of the trial, active vaccine recipients were again randomized to receive one late boost (LB) of CD40.HIVRI.Env (SC, 0.3mg) either with Hiltonol® (1mg) (V+Adj) or not (V-Adj). Safety and immunogenicity (anti Env and anti V1/V2 IgG, Neutralizing antibodies (Nabs), T-cell responses) were evaluated at 2 and 24W after LB (LB+02, LB+24). Results: Forty-five volunteers (mean age 35 years, 56% male) were randomized. Demographics and immune responses were similar between groups at LB visit. LB interval (median; IQR) since VRI06 baseline was 80 W [75;104] in V+Adj (n=22) and 79 W [65;101] in V-Adj (n=23). LB vaccination was safe and well tolerated. IgG response rates (RR) against vaccine-matched (gp140 ZM96) and 9 heterologous gp120/gp140 antigens (Ags) were 50-100% at LB, and 100% and 82-100% at LB+02 and LB+24, respectively. Increases > 1 log 10 in the magnitude of IgG responses (MFI) to Ags were observed at LB+02 relative to LB. RR to gp70 V1V2 Ags raised from 0-4% at LB to 45-55% (autologous 96ZM651), 26-27% (92TH02), 61-68% (CE1086), 61-77% (CaseA2) across groups at LB+02. NAb IC50 titers against Tier1 MW965.26 were detected in 14-22% at LB and 78-95% and 35-59% at LB+02 and +24. Frequencies (median [IQR]) of polyfunctional Env-specific CD4 T cells (IL-2+/-IFN-g+/-TNF) were 0.09 [0.05;0.18] at LB and raised to 0.26 [0.15;0.36] and 0.15 [0.11;0.20] at LB+02 and +24, respectively. No consistent substantial differences were noted between Adj+ and Adj- recipients. Conclusions: Follow-up after initial CD40.HIVRI.Env vaccination showed persistence of immune responses more than one year after the last injection (W26 of the VRI06 trial). A single late boost of CD40.HIVRI.Env, even unadjuvanted, was sufficient to maintain humoral and cellular long-term responses. These results reveal the potency of CD40-DC targeting vaccines to induce durable responses.

427

Augmenting HIV-Specific CAR-T Cell Functionality by Treatment With Novel Cytokine-Based Scaffold Sara Lamcaj 1 , Niraj Shrestha 2 , Zhongyu Zhu 3 , Ying Xiong 3 , Gregory Sowd 3 , Boro Dropulic 3 , Hing Wong 2 , Harris Goldstein 1 1 Albert Einstein College of Medicine, Bronx, NY, USA, 2 HCW Biologics, Miramar, FL, USA, 3 Caring Cross, Gaithersburg, MD, USA Background: We previously described a bispecific CAR-T cell targeting two conserved gp120 epitopes (duoCAR-Ts) with potent anti-HIV activity, now in clinical trials. However, despite ART, many people living with HIV (PLWH) develop systemic inflammation associated with increased levels of TGF-β which may suppress the activity of infused duoCAR-Ts. We hypothesized that inhibiting TGF-β activity may unleash a more potent anti-HIV immune response mediated by our duoCAR-Ts, further amplified by treatment with an IL-15 based fusion molecule. Methods: HCW Biologics developed bifunctional immunomodulatory proteins including HCW9218, composed of TGF-βRII and IL-15/IL-15Rα. TGF-βRII acts as a TGF-β sink, effectively neutralizing its activity and the linked IL-15/IL-15Rα activates NK and CD8+ T cells. As controls, we used HCW9228, composed of TGF-βRII with IL-15/IL-15Rα mutated to reduce activity and HCW9238 with a functional IL-15/IL-15Rα but inactivated TGF-βRII. TGF-β neutralizing activity of HCW proteins were evaluated by treating duoCAR-Ts with HCW proteins and TGF-β, followed by quantifying TGF-β induced-phosphorylation of SMAD2/3. IL-15 function was assessed by staining for IL-15 induced STAT5 phosphorylation in HCW protein treated T cells and measuring cell growth of duoCAR-Ts stimulated with HCWs and TGF-β after 5 days (Fig. 1A). Anti-HIV activity of duo-CAR-Ts in the presence of TGF-β and the HCW proteins was evaluated by cytotoxicity assays targeting 293T-gp120-Luc cells and HIV viral suppression assays using autologous HIV-LucR-infected CD4+ T cells (Fig 1B). Results: TGF-β induced SMAD2/3 phosphorylation was inhibited by HCW9218 but not HCW9238 which lacks functional TGF-βRII. HCW9218 displayed robust IL-15 activity by phosphorylating STAT5 and stimulating proliferation of an IL-15 dependent cell line. HCW9218, but not HCW9228 treatment prevented TGF-β suppression of duoCAR-T cell proliferation (n=4 donors) and HCW9218 IL-15 activity stimulated significantly greater cell growth of duoCAR-Ts compared to HCW9228 treatment (Fig. 1A). duoCAR-Ts treated with TGF-β maintained cytotoxicity and HIV suppression (n=3 donors) in the presence of HCW9218 but not HCW9238 (Fig. 1B). Conclusions: HCW9218 neutralizes TGF-β activity and thereby prevents TGF-β-mediated inhibition of duoCAR-T cell proliferation, cytotoxicity, and HIV suppression. HCW9218 may serve as an adjunct therapy to increase the anti-HIV activity of duoCAR-Ts in PLWH with elevated levels of TGF-β to enable sustained anti-HIV immune responses.

Poster Abstracts

The figure, table, or graphic for this abstract has been removed.

CROI 2025 102