BackgroundOvercoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. AMV564 is a potent conditional agonist that engages T cells to selectively deplete target cells such as MDSC while promoting T cell polarization and activation. Whereas CD33 plays an insignificant role in differentiated myeloid cells, CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data1 as well as data from a clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to selectively deplete MDSC while sparing monocytes and neutrophils.2 3MethodsNCT04128423 is a multi-center Phase 1 study to determine the safety and tolerability, define the maximum-tolerated or pharmacologically active dose, and assess the preliminary efficacy of AMV564. In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection on Days 1–5 and 8–12 of a 21-day cycle. Primary endpoints include incidence, nature and severity of adverse events (AEs). Secondary endpoints include assessment of pharmacokinetics and pharmacodynamics.ResultsAs of June 30, 2020, 11 patients have been dosed across 3 dose cohorts (15 mcg – 75 mcg). The tumor types enrolled were: colorectal (n=2), GE junction (n=2), pancreatic (n=2), squamous cell carcinoma (n=2), small intestine, ovarian, and endometrial cancer. AMV564 has been well tolerated with no dose-limiting toxicities. The most common treatment-related AEs were fever/pyrexia (Grade 1: n=3; Grade 2: n=8) and injection site reactions (Grade 1: n=1; Grade 2: n=9). Preliminary estimate of median plasma half-life for AMV564 after SC injection was >48 hours, with dose-related increases in peak plasma concentration (Cmax). Tumor responses were evaluable in 9 patients; 1 patient had not reached their first assessment and 1 patient was not efficacy evaluable due to a non-treatment-related AE resulting in study discontinuation. Single-agent activity has been observed including a complete response by RECISTv1.1 criteria in 1 patient with ovarian cancer refractory to all standard therapies and anti-PD-1 therapy, and stable disease in 4 additional patients.ConclusionsAMV564 has been well tolerated across multiple dose levels, with good plasma exposure and evidence of anti-tumor activity when administered subcutaneously. Single-agent anti-tumor activity was observed in an ovarian cancer patient.AcknowledgementsWe would like to thank the patients and their families for participating in this clinical trial.Trial RegistrationNCT04128423Ethics ApprovalThe study was approved by the Institutional Review Board at each center where the study is being conducted.ReferencesCheng P, Eksioglu E, Chen X, et al. Immunodepletion of MDSC By AMV564, a novel Tetravalent bispecific CD33/CD3 T cell engager restores immune homeostasis in MDS in Vitro. Blood. 2017; 130:51 (abstract).Eckard S, Gehrs L, Smith V, et al. AMV564, a novel bivalent, bispecific T-cell engager, targets myeloid-derived suppressor cells. SITC Annual Meeting; 2019 Nov 6-10. Oral Presentation O71.Westervelt P, Roboz G, Cortes J, et al. Safety and Clinical Activity of AMV564, a CD33/CD3 T-cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML): Updated Results from the Phase 1 First-in-Human Trial. EHA Annual Congress; 2019 Jun 13-16. Abstract S877.
HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment