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2533 Background: Most solid tumors are resistant to immunotherapy. In pre-clinical studies, CAR-M infiltrate tumors, phagocytose tumor cells, activate the tumor micro environment (TME), recruit T cells, and present tumor antigens to T cells leading to robust anti-tumor immunity. CT-0508 is a first in class CAR-M, comprised of autologous monocyte derived macrophages expressing an anti-HER2 CAR. Here we present preliminary clinical results from the CT-0508 Phase 1 FIH study. Methods: This multi-center, open-label study is evaluating CT-0508’s safety, tolerability, and manufacturing feasibility in 18 participants (pts) with advanced solid tumors overexpressing HER2 who have progressed on prior therapies. Monocytes are isolated from mobilized apheresis products, differentiated into macrophages and engineered with an anti-HER2 CAR. Group 1 pts (n = 9) receive a fractionated dose (D1, D3, D5) and Group 2 pts (n = 9) receive the full dose on D1. CT-0508 is administered without preparative chemotherapy (bridging is permitted). Serial blood samples, 1 pre and 2 post-treatment biopsies are collected to investigate safety, pharmacokinetics and mechanism of action. Results: Seven pts (4F/3M), median age 64 (49-73), have been treated [breast (2), esophageal (2), cholangiocarcinoma, ovarian and parotid gland cancers]. A median of 3 (2-10) prior lines of therapy have been administered, most pts (85.7%) received prior anti HER2 therapy. CT-0508 was successfully manufactured with high viability, purity and CAR expression, and was well tolerated with no dose limiting toxicities or AEs leading to discontinuation or dose modification. Two related SAEs were reported in the same pt (Grade 1 CRS, hospitalized for monitoring and Grade 2 infusion reaction, resolved within 1h). Three other pts had Grade 1-2 CRS; resolved within 4d with no use of tocilizumab needed. There were no major organ toxicities and no on-target off-tumor toxicities. Post-infusion cytokines were transiently elevated in most pts and were self-limiting. Among the 4 pts who reached week 8, the best overall response was stable disease (n = 3) and 1 pt progressed, with a median follow up of 8w. CT-0508 rapidly egressed from peripheral blood. CT-0508 CAR mRNA was detected in all tumor biopsies of the first 2 pts. CT-0508 activated the TME, with increased myeloid cell activation, T cell infiltration, activation and proliferation. TCR sequencing demonstrated peripherally expanding T cells enriched for tumor infiltrating lymphocyte clones, suggesting expansion of tumor reactive T cells. Correlative data from additional pts will be presented. Conclusions: In 7 pts, CT-0508 was safe and feasible to manufacture. Early correlative data demonstrate trafficking, TME modulation, and potential induction of anti-tumor T cell immunity. The study is actively enrolling. Clinical trial information: NCT04660929.

TPS2677 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. [Table: see text]