Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically evince immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR confers on the macrophages the ability to selectively recognize and phagocytose antigen overexpressing cancer cells. Additionally, CAR macrophages reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory.

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in many cancers, including but not limited to breast and gastroesophageal cancers.

CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory 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 and prolonged survival in relevant models. CT-0508 cells were safe in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer.

Methods: This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in approximately 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 who have failed available therapies including anti-HER2 therapies when indicated.

Filgrastim will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. The CT-0508 CAR macrophage product will be manufactured, prepared and cryopreserved from mobilized peripheral blood monocytes.

Group 1 subjects will receive CT-0508 infusion split over D1, 3 and 5. Subjects will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be observed and addressed by a Safety Review Committee.

Group 2 subjects 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 (PCR, RNA scope), persistence, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others.

Clinical trial registry number: NCT04660929

Citation Format: Joshua Bauml, Debora Barton, Amy Ronczka, Daniel Cushing, Michael Klichinsky, Elizabeth C. Dees. A phase 1, first in human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT204.