CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial

Chimeric antigen receptor (CAR) macrophages (CAR-Ms) mediate antitumor immunity via phagocytosis, cytokine release, activation of the tumor microenvironment and antigen presentation. We report results from a non-prespecified interim analysis of a first-in-human, phase 1 clinical trial of CT-0508, an anti-human epidermal growth factor receptor 2 (HER2) CAR-M in patients with advanced HER2-overexpressing tumors. Fourteen patients were treated across two different regimens. Patients with breast cancer and gastroesophageal cancer were primarily enrolled and had to have demonstrated overexpression of HER2 according to the American Society of Clinical Oncology/College of American Pathologists guidelines (HER2 immunohistochemistry 3+ or immunohistochemistry 2+/in situ hybridization-amplified). No lymphodepletion chemotherapy was used before infusion. The primary endpoints were safety and CAR-M manufacturability. Secondary endpoints included cellular kinetics and efficacy using objective response rate, overall survival, progression-free survival and duration of response. No dose-limiting toxicities, severe cytokine release syndrome (≥grade 3) or immune effector cell-associated neurotoxicity syndrome were observed; 44% (n = 4 of 9, 95% confidence interval = 14–79%) of HER2 3+ tumors achieved stable disease as best overall response 8 weeks after treatment. No meaningful activity was observed in the HER2 2+ population (n = 5). Correlative analyses of serial biopsies confirmed that CT-0508 traffics to and remodels the tumor microenvironment, resulting in expansion of CD8⁺ T cells. These findings demonstrate the preliminary safety, tolerability and manufacturing feasibility of CT-0508 for HER2⁺ tumors. ClinicalTrials.gov registration: NCT04660929.