Background: Although immune checkpoint inhibitors (CPIs) have revolutionized cancer treatment, resistance remains a challenge. Reduced interferon (IFN) signaling, immune escape and immunosuppressive tumor phenotypes have been proposed as resistance mechanisms, suggesting innate immune cell stimulation in the tumor microenvironment as a potential strategy to overcome resistance. Stimulator of Interferon Genes (STING) is a cytosolic protein critical for induction of type 1 IFN-dependent innate immunity. Cysteine-cysteine chemokine receptor type 2 (CCR2) is expressed by tumor-infiltrating myeloid cells, including tumor associated macrophages (TAM), and promotes immune escape by limiting CD8+ T-cell infiltration. TAK-500 is an ISAC that consists of three parts: a STING agonist payload based on TAK-676 (currently under phase 1 clinical evaluation [NCT04420884, NCT04879849]), the IgG1 anti-CCR2 antibody (previously evaluated in early phase studies), and a self-immolating maleimide-containing protease-cleavable peptide linker. By targeting STING to CCR2 expressing myeloid cells, TAK-500 has three possible mechanisms of action: activation of IFN response, reprogramming of suppressive intratumoral CCR2+ cells to an inflammatory phenotype, and blockade of suppressive TAM recruitment. TAK-500 thus has the potential to overcome resistance to CPIs in both CPI refractory and immunologically excluded or deserted tumors. Methods: This phase 1a/1b open-label study (NCT05070247) will evaluate the safety, tolerability, antitumor activity, pharmacokinetics and pharmacodynamics of TAK-500 in patients aged ≥18 years with gastroesophageal adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, non-squamous non-small cell lung cancer, squamous cell carcinoma of the head and neck, mesothelioma or triple-negative breast cancer. Patients must have had progressive disease or intolerance to all standard therapy. In the initial dose escalation phase, patients will receive single-agent intravenous (IV) TAK-500 administered once every 3 weeks (Q3W) in 21-day cycles to determine the pharmacologically active dose (PAD) range. An additional escalation cohort will receive TAK-500 in combination with IV pembrolizumab 200 mg Q3W in 21-day cycles, with the initial TAK-500 dose level beginning 1-2 dose levels below the predicted single agent PAD range. Dose escalation in both single agent and combination cohorts will be guided by the Bayesian Optimal Interval design. A subsequent dose expansion phase will evaluate TAK-500 in combination with pembrolizumab. Planned enrollment for both escalation and expansion cohorts is ~106 patients. Citation Format: Jennifer R. Diamond, Jason T. Henry, Gerald S. Falchook, Anthony J. Olszanski, Harshabad Singh, E. Jane Leonard, Richard C. Gregory, Vicky A. Appleman, John P. Gibbs, Carole E. Harbison, Cong Li, Jessica M. Sapiro, Tomoki Yoneyama, Alexander Parent, Vincent Chung. First-in-human study of TAK-500, a novel STING agonist immune stimulating antibody conjugate (ISAC), alone and in combination with pembrolizumab in patients with select advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT249.
TPS2690 Background: Tumor resistance to immune checkpoint inhibitors (CPIs), including pembrolizumab, is common. Suggested mechanisms of resistance include reduced interferon (IFN) signaling, immune escape, and immunosuppressive tumor phenotypes. Innate immune cell stimulation in the tumor microenvironment may be a potential pathway to overcome this resistance. Stimulator of interferon genes (STING) is a cytosolic protein critical for initiation of type-1 IFN-dependent innate immunity. TAK-500 is a novel ISAC comprising a STING agonist (based on TAK-676, which is currently in phase 1 clinical trials [NCT04420884, NCT04879849]), an IgG1 anti-cysteine-cysteine chemokine receptor 2 (CCR2) antibody, and a self-immolating maleimide-containing protease-cleavable peptide linker. CCR2-expressing myeloid cells, including tumor associated macrophages (TAMs), promote immune evasion in part by reducing infiltration of CD8+ T cells into the tumor microenvironment. As such, TAK-500 has the potential to mitigate CPI resistance in solid tumors via targeted STING activation of tumor-infiltrating CCR2-expressing myeloid cells, thus leading to stimulation of innate and adaptive immunity within the tumor microenvironment through three potential mechanisms of action: activation of IFN signaling, reprogramming of CCR2-expressing myeloid cells to an inflammatory phenotype, and blockade of suppressive TAM recruitment. Methods: Adult patients with a diagnosis of locally advanced or metastatic gastroesophageal adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, non-squamous non-small cell lung cancer, squamous cell carcinoma of the head and neck, mesothelioma or triple-negative breast cancer are eligible. All patients must have progressive disease while on, or be intolerant to, all current standard therapies. Approximately 106 patients in total will be enrolled to the dose escalation and expansion cohorts. In the dose escalation phase, intravenous (IV) TAK-500 will be administered over the range 8–480 µg/kg on day 1 of every 21-day cycle (Q3W) to establish the pharmacologically active dose (PAD) range. An additional escalation cohort of patients will receive TAK-500 + IV pembrolizumab 200 mg Q3W, starting at a dose of TAK-500 that is 1–2 dose levels below the lowest PAD range established in the single agent cohort. Dose escalation in both cohorts will be guided by Bayesian Optimal Interval design. In the dose expansion phase, only the combination of TAK-500 + pembrolizumab will be evaluated. Primary objectives of this study are safety and tolerability; secondary objectives include determination of the PAD range, the recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and antitumor activity of TAK-500 as a single agent and in combination with pembrolizumab. Clinical trial information: NCT05070247.
Although all--retinoic acid (ATRA) provides protection against a variety of conditions in vivo, particularly ischemia, the molecular mechanisms underpinning these effects remain unclear. The present studies were designed to assess potential mechanisms by which ATRA affords cytoprotection against renal toxicants in LLC-PK cells. Pretreatment of LLC-PK cells with ATRA (25 μM) for 24 h afforded cytoprotection against oncotic cell death induced by -aminophenol (PAP), 2-(glutathion--yl)hydroquinone (MGHQ), and iodoacetamide but not against apoptotic cell death induced by cisplatin. Inhibition of protein synthesis with cycloheximide blunted ATRA protection, indicating essential cell survival pathways must be engaged before toxicant exposure to provide cytoprotection. Interestingly, ATRA did not prevent the PAP-induced generation of reactive oxygen species (ROS) nor did it alter glutathione levels. Moreover, ATRA had no significant effect on Nrf2 protein expression, and the Nrf2 inducers sulforaphane and MG132 did not influence ATRA cytoprotection, suggesting cytoprotective pathways beyond those that influence ROS levels contribute to ATRA protection. In contrast, ATRA rapidly (15 min) induced levels of the cellular stress kinases -ERK and-AKT at concentrations of ATRA (10 and 25 μM) required for cytoprotection. Consistent with a role for -ERK in ATRA-mediated cytoprotection, inhibition of-ERK with PD98059 reduced the ability of ATRA to afford protection against PAP toxicity. Collectively, these data suggest that -ERK and its downstream targets, independent of ROS and antioxidant signaling, are important contributors to the cytoprotective effects of ATRA against oncotic cell death.
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