BackgroundA research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH).MethodsUnmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and 64Cu (64Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial 64Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg 64Cu-3BNC117) and trace (<5mg 64Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for 64Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract).FindingsComparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that 64Cu-3BNC117 remained intact in vivo.InterpretationIn PLWH on or off ART, the intervention of infusing 64Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo.FundingFunded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (USAI126611). JHM and SRL are supported by the Australian National Health and Medical Research Council.
Abstract Background and Purpose: Immune checkpoint therapy (ICT) has revolutionized cancer treatment; however, efficacy remains poor for some cancers, including small cell lung cancer (SCLC). Strategies to enhance immune responses include combining ICT with other existing cancer therapies. Targeted radioligand therapy uses a radiolabeled cancer-targeting vector, allowing for specific delivery of radiation to all tumor sites while minimizing radiation exposure to healthy tissues. Targeted Copper Theranostics (TCTs) is a targeted radioligand platform utilizing copper-64/67. We evaluated [67Cu]Cu-SARTATE in combination with ICT in a murine animal model using RP116 tumor cells. Methods: We administrated ∼5 MBq [64Cu]Cu-SARTATE to RP116 (a murine SCLC cell line expressing SSTR2) tumor- bearing immunocompetent C57BL/6 mice and assessed biodistribution and tumor uptake via PET imaging at 1, 4 and 24 h post IV injection. After completion of a dose escalation study, an efficacy study using [67Cu]Cu-SARTATE, mouse ICT analogues and the combination of [67Cu]Cu-SARTATE and ICT treatment groups in the same animal model was performed to evaluate therapeutic efficacy of copper-67-based TCT. Results: Tumor uptake of [64Cu]Cu-SARTATE was visualized by PET imaging over the first 24 h post-injection with high tumor uptake, consistent with multiple studies previously published showing uptake in human xenograft models with the same product. Tumor uptake of [67Cu]Cu-SARTATE was confirmed by ex vivo biodistribution and Cherenkov imaging, with no significant radiotoxicity observed via body condition and body weight measurements in mice receiving injected activities up to the maximum tested dose of 30 MBq. The combination of 30 MBq [67Cu]Cu-SARTATE, with both anti-PD-L1 and anti-CTLA4, improved median survival by 3, 7, or 13 days, compared to ICT-only (anti-PD-L1 plus anti-CTLA4), [67Cu]Cu-SARTATE-only or saline-only treated groups respectively. Conclusion: Biodistribution studies demonstrated high tumor-specific uptake for [64Cu]- and [67Cu]-Cu-SARTATE in this mouse syngeneic SCLC model. A dose escalation study demonstrated copper-67-based TCT could be used to effectively inhibit tumor growth with minimal radiotoxicity. The combination of TCT with ICTs improved overall survival compared to single-treatment control groups. Collectively, our results demonstrate that [67Cu]Cu-SARTATE in combination with ICTs improves overall survival. [67Cu]Cu-SARTATE may prime immunologically “cold” SCLC tumors to improve responsiveness to ICTs through a synergistic response. Tumor biomarkers are being investigated to understand how immune infiltration differs depending on treatment regime. Citation Format: Jaclyn L. Lange, Kurt R. Gehlsen, Lachlan E. McInnes, Jessica Van Zuylekom, Benjamin Blyth, Stacey E. Rudd, Paul S. Donnelly, Matt Harris. Copper-67 based targeted radioligand therapy to the somatostatin receptor 2 (SSTR2) provides added efficacy and may prime small cell lung cancer for immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B005.
Introduction Epstein‐Barr virus (EBV) viraemia is associated with nasopharyngeal carcinoma and lymphoproliferative diseases. In HIV‐1 infection, persistent EBV viraemia is a common phenomenon. The underlying mechanism of these high EBV DNA loads has not been clarified. We studied EBV viraemia during primary HIV‐1 infection (PHI) to explore the mechanism of EBV viraemia in HIV‐1 infection. Methods Patients with PHI, participating in Primo‐SHM study, a clinical trial with three study arms: no treatment, 24 weeks of combination antiretroviral therapy (cART) and 60 weeks of cART, were sampled longitudinally during PHI and 24 and 48 weeks thereafter. EBV DNA was assayed by PCR on stored samples of lysed whole blood. Results 39 patients were tested, in 22 of whom EBV DNA was detected at one or more time points. All patients tested positive for anti‐VCA and anti‐EBNA antibodies, most patients that had EBV viraemia did not receive cART or interrupted cART. The prevalence of EBV viraemia at baseline was 29%, 18% and 33% for the untreated, 24 weeks cART and continuous cART groups. At week 48, these percentages were 38, 64 and 17 respectively (p < 0.05). Individual concentrations of EBV DNA for the three groups are shown in Figure 1 . The Black lines show the individual log10 transformed EBV DNA concentrations in whole blood in patients that remained untreated (panel a), patients that were treated for 24 weeks with cART (panel b) and patients that were treated continuously with cART (Panel c). image Conclusion Intermittent EBV viraemia is highly prevalent in patients with PHI. Assuming that patients with very early HIV‐1 infection are still immunocompetent, this indicates that EBV viraemia is not caused by immunodeficiency. Antiretroviral therapy started during PHI but not later during chronic HIV infection might reduce the prevalence of EBV viraemia in HIV‐1 infection.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
PEG(5)-BP–BaYbF 5 nanoparticles provide superior CT contrast and circulation time compared to clinically-used iodinated molecules, but suffer from unexpected in vivo toxicity.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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