Abstract CT249: 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
Authors: Diamond Jennifer R. , Henry Jason T. , Falchook Gerald S. , Olszanski Anthony J. , Singh Harshabad , Leonard E. Jane , Gregory Richard C. , Appleman Vicky A. , Gibbs John P. , Harbison Carole E. , Li Cong , Sapiro Jessica M. , Yoneyama Tomoki , Parent Alexander , Chung Vincent 
Published: June 2022

Abstract
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.