MYE Symphony: A first-in-human study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the in vivo mRNA CAR therapy, MT-302, targeting TROP2 in adults with advanced epithelial tumors

BackgroundThis is the first clinical trial of an in vivo chimeric antigen receptor (CAR) therapy. The in vivo approach, with repeat dosing and no conditioning, has the potential to overcome many of the challenges of ex vivo CAR therapies. MT-302, an mRNA-lipid nanoparticle (LNP) formulation for intravenous delivery, allows for dose and schedule optimization. The mRNA encodes for a receptor consisting of a TROP2-targeted scFv, as well as the transmembrane domain and cytoplasmic tail of CD89. Upon MT-302 dosing the LNP is taken up by numerous cell types, but a functional CAR can only be expressed on the surface of cells that also express the Fc receptor common gamma chain, predominately myeloid cells. In vivo delivered MT-302 resulted in TROP2 CAR expression and anti-tumor efficacy in an HCC-1954 breast cancer xenograft model (Argueta, AACR 2024, #1321). In a syngeneic model, in vivo delivered surrogate CD89-based CAR treatment inhibited tumor growth with demonstrated intra-tumoral accumulation of activated CD8+ T cells and reduced tumor associated Tregs (Prod'homme, AACR 2023, LB027). Thus, this first-in-class in vivo CAR-M (myeloid) therapy will be tested to treat TROP2 expressing cancers with the goal of infiltrating the tumor microenvironment and initiating a broad anti-tumor immune response.Trial designMYE Symphony is a multicenter first-in-human study of MT-302 in participants with advanced epithelial cancers enriched for high TROP2 expression. MT-302 is given every 14 days for 3 doses followed by administration once every 28 days. The dose escalation employs a Bayesian Optimal Interval design with backfill for further dose evaluation. Primary endpoints are to assess safety and define the MTD and RP2D. Secondary endpoints include defining the PK and rates of ICANs and CRS. Exploratory endpoints include efficacy measures (e.g. ORR and DOR) and treatment induced immunologic impact (e.g. peripheral CAR expression, cytokine release, and T cell receptor clonality, as well as changes in the tumor immune environment and TROP2 expression). The first three dose level cohorts have been enrolled. NCT05969041.Legal entity responsible for the studyMyeloid Therapeutics.FundingMyeloid Therapeutics.DisclosureM. Churchill, M. Barnett, M. Cioffi: Financial Interests, Personal and Institutional, Full or part-time Employment: Myeloid Therapeutics. All other authors have declared no conflicts of interest.