Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but have had less success in those with solid tumors. Macrophages are actively recruited and abundantly present in the solid tumor microenvironment (sTME). Tumor associated macrophages are predominantly immunosuppressive and support tumor growth (M2), while a subset of proinflammatory macrophages enhance anti-tumor immunogenicity (M1). M1 macrophage function can be augmented by CAR expression to selectively recognize and phagocytose antigen overexpressing cancer cells. Moreover, CAR macrophages can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many solid tumors (Table). CT-0508 is a cell product comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pt) with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2. Pt previously treated with available therapies, including anti-HER2 therapies, as indicated, and subsequent progression are permitted. Filgrastim is used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 is manufactured, prepared, and cryopreserved from mobilized peripheral blood monocytes. Group 1 pt (n=9) receive CT-0508 infusion split over D1, 3, and 5. A Safety Review Committee will review dose limiting toxicities. Group 2 pt (n=9) will receive the full CT-0508 infusion on D1. Pre- and post-treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Radiographic imaging is also being conducted to assess preliminary tumor activity. Clinical trial information: NCT04660929.