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Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Background Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. Methods In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. Measurements and main results An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. Conclusions Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

BackgroundTumour necrosis factor (TNF) is upregulated in the alveolar space early in the course of ventilator-induced lung injury (VILI). Studies in genetically modified mice indicate that the two TNF receptors play opposing roles during injurious high-stretch mechanical ventilation, with p55 promoting but p75 preventing pulmonary oedema.AimTo investigate the effects of selective inhibition of intra-alveolar p55 TNF receptor on pulmonary oedema and inflammation during ventilator-induced lung injury using a newly developed domain antibody.MethodsAnaesthetised mice were ventilated with high tidal volume and given an intratracheal bolus of p55-specific domain antibody or anti-TNF monoclonal antibody (‘pure’ VILI model). As a model of enhanced inflammation, a subclinical dose of lipopolysaccharide (LPS) was included in the intratracheal antibody bolus (LPS+VILI model). Development of lung injury was assessed by respiratory mechanics and blood gases and protein levels in lavage fluid. Flow cytometry was used to determine leucocyte recruitment and alveolar macrophage activation, while lavage fluid cytokines were assessed by ELISA.ResultsThe ventilation protocol produced deteriorations in respiratory mechanics and gas exchange with increased lavage fluid protein levels in the two models. The p55-specific domain antibody substantially attenuated all of these changes in the ‘pure’ VILI model, while anti-TNF antibody was ineffective. In the LPS+VILI model, p55 blockade prevented deteriorations in respiratory mechanics and oxygenation and significantly decreased neutrophil recruitment, expression of intercellular adhesion molecule 1 on alveolar macrophages, and interleukin 6 and monocyte chemotactic protein 1 levels in lavage fluid.ConclusionsSelective inhibition of intra-alveolar p55 TNF receptor signalling by domain antibodies may open new therapeutic approaches for ventilated patients with acute lung injury.

BackgroundImmune checkpoint blockade (ICB) treatment, alone or in combination with standard anticancer therapies, has led to important progress in the treatment of head and neck squamous cell carcinoma (HNSCC). Yet, a significant proportion of patients with carcinogen-associated HNSCC (human papillomavirus (HPV)−) develop disease relapse or progression. Effective treatments for patients who have failed standard of care (SOC) treatment are lacking. STAR0602, a selective, bifunctional T cell agonist comprising an antibody targeting Vβ6 and Vβ10 T cell receptors fused to human interleukin-2, has demonstrated clinical activity in anti-programmed death-ligand 1 resistant tumors. A murine surrogate molecule, mSTAR1302, has been shown to induce tumor regression in multiple syngeneic tumor models and enhance antitumor activity in ICB-refractory settings. This study investigates the therapeutic benefit of mSTAR1302 combined with SOC in the mouse oral carcinoma (MOC)1 and MOC2 HNSCC tumor models.MethodsC57BL/6 mice bearing MOC1 or MOC2 tumors were treated weekly with mSTAR1302, cisplatin, and α-programmed cell death protein 1 (PD-1) antibody to determine antitumor efficacy and survival benefit. Immune populations and their effector functions were characterized by flow cytometry and cytokine assays. The tumor microenvironment’s immune architecture was analyzed by multiplex immunofluorescence. Gene expression analysis was conducted to gain an understanding of the mechanism of action of the combination therapy.ResultsCombination therapy with mSTAR1302, cisplatin, and α-PD-1 promoted robust antitumor activity, higher numbers of mice with complete resolution of tumors, and significantly prolonged survival compared with mSTAR1302 monotherapy or SOC treatment in MOC1 and MOC2 tumors. Tumor-free animals from cohorts treated with the combination therapy demonstrated protection against tumor rechallenge and an overall increase in antigen-specific T cells. Tumor growth inhibition was associated with the expansion of Vβ13 CD8+ and CD4+ T cells, characterized by heightened cytotoxic and effector potentials, in both the tumor and the periphery. The therapeutic effect elicited by the combination therapy was strongly dependent on interferon-γ expression. Thus, the combination of mSTAR1302 and α-PD-1 enabled control of tumors that progressed following platinum-containing treatment.ConclusionThese findings provide a rationale for the combination of STAR0602 and SOC therapy in the clinical setting for patients with recurrent or metastatic HPV− HNSCC.

Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment. We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting \"dummy\" dAb, 1 or 4 h before acid instillation. Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase. These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.

BackgroundLung adenocarcinoma is the leading cause of cancer-related deaths nationally and worldwide. An unmet clinical need exists to overcome therapy resistance in metastatic lung cancer patients treated with the standard of care platinum-based chemotherapy combined with immune checkpoint blockade (ICB) using antibodies against the programmed cell death protein 1 (PD-1) or its ligand (PD-L1). To this end, we are evaluating the anti-tumor efficacy of a novel, bifunctional fusion molecule, mSTAR1302, comprised of an activating antibody that binds the murine variable beta 13 (Vβ13) chain of the T cell receptor (TCR), and is fused to interleukin-2 (IL-2). The Vβ13 TCR T cells were identified as a common subpopulation of tumor infiltrating T cells in various mouse tumor models. We aim to assess the preclinical use of mSTAR1302 in combination with ICB in syngeneic lung cancer models that are resistant to PD-1 blockade and platinum-based chemotherapy.MethodsThe CMT64 lung cancer model was characterized for its response to anti-PD1 therapy alone or in combination with cisplatin. Subsequent studies assessed the antitumor activity of mSTAR1302 combined with anti-PD1 therapy delivered three days after mSTAR1302 administration. Tumor volumes, survival, and toxicity data were collected. Additionally, flow cytometry analysis was used to assess Vβ13 TCR T cell expansion and alterations in the tumor microenvironment immune profile.ResultsOur initial results demonstrated CMT64 tumor’s lack of response to anti-PD-1 or cisplatin alone and a minimal response to the combination. Subsequent experiments evaluated mSTAR1302 plus anti-PD1. While anti-PD1 had no effect, mSTAR1302 monotherapy delayed tumor growth in 50% of mice with no cures observed. The combination mSTAR1302 plus anti-PD-1 demonstrated additive effect leading to delayed tumor growth in 100% of treated mice with complete tumor regression achieved in 50% of mice. Survival of mice in the combination therapy group was significantly increased over that of mice in the monotherapy and control groups. Flow cytometry analysis on tumors showed significant increases in tumor infiltrating CD4, CD8, and NK cell numbers in the combination group, with an expansion of Vβ13 TCR CD8 T cells. Rechallenge experiments and transcriptomics analyses are ongoing to identify the mechanism of action.ConclusionsThis study serves as a proof of concept that targeting and expanding Vβ13 TCR tumor infiltrating T cells via mSTAR1302 is a promising approach to treat poorly infiltrated tumors resistant to checkpoint blockade. Future studies will expand testing in additional models, various administration schedules, and the addition of chemotherapy.Ethics ApprovalAll animal studies were approved by the NIH Intramural Animal Care and Use Committee.

Preclinical and early clinical studies suggest that angiotensin‐converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin‐converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi‐center, open‐label, exploratory, single‐dose, dose‐escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin‐angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1–7) and angiotensin (1–5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.

BackgroundTumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects.MethodsWe investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin.ResultsSelective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples.ConclusionThese data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome.Trial registration numberClinicalTrials.gov NCT01587807.

BackgroundWe have previously shown that novel bifunctional ‘STAR’ antibody-fusion molecules comprising germline b chain TCR-targeting agonist antibodies fused to costimulatory cytokines co-engage the TCR and T cell cytokine receptors, thereby promoting expansion of subsets of T cells expressing distinct germline variable b (Vb) chain TCRs. Here we describe a new class of T cell engager (TriSTAR) that utilizes a tri-specific format comprising the ‘STAR’ TCR b chain antibody agonist and IL-2 fusion module coupled to an additional Fab arm targeting tumor associated antigens. By design, TriSTAR molecules promote the selective activation and expansion of Vb T cell subsets that adopt a novel memory-like effector phenotype and are re-targeted to tumors. TriSTAR0701, a human Nectin-4 (hN4)-targeting TriSTAR molecule induced potent and durable anti-tumor activity in mice bearing refractory solid tumors expressing hN4.MethodsTriSTAR0701 constructs with optimized affinities to hN4 and TCRVb were generated and tested in vitro and in vivo in relevant hN4-expressing tumor cell lines and murine transgenic tumor models expressing hN4, respectively. In mouse and cynomolgus monkey models, the pharmacology of TriSTAR0701 were assessed using flow cytometry, NanoString and other immunoassays.ResultsTriSTAR0701 elicited potent in vitro activation and expansion of human Vβ6/10 T cells that adopted a characteristic memory-like effector phenotype. In human in vitro T cell/cancer cell co-cultures, these constructs also induced potent cytotoxicity of hN4-expressing tumor lines across a range of hN4 expression levels. In cynomolgus monkeys and murine tumor-bearing mice TriSTAR0701 molecules were efficiently distributed and induced expected pharmacology in target compartments. In mice, TriSTAR0701 accumulated in tumors and induced potent anti-tumor activity that was superior to untargeted STAR T cell activators and hN4-targeting anti-CD3 TCEs. This superior anti-tumor activity was attributed to accumulation of CD8+, CD25+ and Granzyme B+ T cells within expanded Vβ T cell subsets in tumors. Further immune profiling using flow cytometry and gene expression assays in tumors and blood isolated from treated mice highlighted significant remodeling of tumor-infiltrating lymphocyte (TIL) populations.ConclusionsGermline b chain TCR-targeting TriSTAR molecules represent a new class of selective T cell engager with the potential to redirect Vβ T cell subsets with a memory phenotype to tumors resulting in improved anti-tumor activity compared with established anti-CD3 T cell engagers. Here we show that TriSTAR0701, a hN4-targeting TCE, drives potent anti-tumor activity in human in vitro and murine in vivo models making them a promising emerging treatment modality for hN4-expressing solid tumors.

BackgroundDespite the success of immune checkpoint blockade (ICB) in treating solid tumors, only a proportion of patients respond, and there is need to develop therapies to improve the quantity and quality of T cell responses. Accumulation in tumor draining lymph node and tumor of stem-like memory T cells (TSCM) or T cells expressing TCF1, a transcription factor critical in self-renewal, is important for tumor control with ICB; these tissues, however, are not easily accessible. We determined whether TSCM were present and induced in peripheral blood of cancer patients receiving invikafusp alfa (STAR0602), a first-in-class bifunctional fusion protein that simultaneously engages a nonclonal mode of T cell receptor activation with IL-2R costimulation to promote selective activation/expansion of Vβ6/Vβ10 T cells, which are prevalent across human cancers.1 Early data from START-001 (NCT05592626), an ongoing multicenter Phase 1/2 trial evaluating STAR0602 in ICB-resistant, antigen-rich tumors, demonstrated a manageable safety profile, and promising anti-tumor activity.2 Here, we characterize peripheral immune changes, including impacts on TSCM, in a subset of patients enrolled in START-001.MethodsComprehensive immune profiling was performed in peripheral blood serially collected from 10 patients in the dose escalation of START-001 (with HPV associated (n=7), esophageal (n=1), and colorectal (n=2) cancers). Complete blood counts, PBMC subsets, HPV-16-specific T cells, serum analytes, and circulating tumor DNA (ctDNA) were analyzed.ResultsSTAR0602 expanded absolute lymphocyte and eosinophil counts, and frequencies of total CD8+ T cells. Consistent with preclinical studies, STAR0602 selectively expanded Vβ6/Vβ10 CD4+ and CD8+ T cells with central memory and effector memory phenotypes, and selectively increased T cells expressing PD-1 and Granzyme B. STAR0602 notably promoted peripheral T cell stemness, as indicated by upregulation of frequencies of TSCM, and TSCM and central and effector memory T cells expressing TCF1 in Vβ6/Vβ10 subsets. STAR0602 induced serum levels of multiple pro-inflammatory cytokines, T cell attracting chemokines, and soluble immune checkpoints. Selected patients displayed expansion of HPV-16-specific T cells, and reduction in ctDNA levels, suggestive of a tumor response to treatment.ConclusionsSTAR0602 induces dynamic immune activation, promoting the potent and selective activation and expansion of Vβ6/Vβ10 CD4+ and CD8+ T cells, and leads to ctDNA decrease and expansion of antigen-specific T cells. Moreover, we demonstrate that STAR0602 boosts peripheral T cells with stem-like and activated characteristics. Further studies combining STAR0602 with other immunotherapeutic agents to synergize with this peripheral burst of T cell stemness are warranted.ReferencesHsu J, Donahue RN, Katragadda M, Lowry J, Huang W, Srinivasan K, Guntas G, Tang J, Servattalab R, Moisan J, Tsai YT, Stoop A, Palakurthi S, Chopra R, Liu K, Wherry EJ, Su Z, Gulley JL, Bayliffe A, Schlom J. A T cell receptor β chain-directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity. Sci Transl Med. 2023;15:eadi0258.Gulley JL, Sullivan RJ, Friedman CF, Sonpavde GP, Tschernia NP, Herrera M, Marabelle A, McCue S, Srinivasan K, Katragadda M, Moisan J, Bayliffe A, Chopra R, Chin K, Su Z, Liu K, Siu LL. 1470-START001: a phase 1/2 study of invikafusp alfa (STAR0602), a first-in-class TCR β chain-targeted bispecific antibody, as monotherapy in patients with antigen-rich solid tumors resistant to anti-PD(L)1: Journal for ImmunoTherapy of Cancer. 2024;12.Ethics ApprovalAll subjects gave written informed consent. Study protocol (NCT05592626) was approved by the NIH’s IRB, and conducted in accordance with institutional and federal guidelines.