Myeloid Therapeutics' novel GPC3-targeting chimeric antigen receptor (CAR) mRNA/lipid nanoparticle formulation, MT-303, is under investigation as a potential therapeutic option for hepatocellular carcinoma (HCC). The agent is designed to enable myeloid cells to directly target and kill tumor cells while supporting a cytokine-mediated immune response. A Phase 1 trial (NCT06478693) is currently underway to evaluate MT-303 in patients with HCC.
Mechanism of Action and Preclinical Data
MT-303 comprises a GPC3-specific single-chain variable fragment fused with a truncated human CD89. Preclinical studies focused on characterizing the expression and function of the GPC3 CAR in vitro. Initial mRNA constructs exhibited limited CAR expression duration, which led to modifications in the coding sequence and 3’UTR. These changes significantly enhanced the expression level and duration of CAR on monocytes, leading to improved cytokine production and tumor cytotoxicity in vitro.
In a HepG2 HCC xenograft model, the optimized mRNA construct demonstrated higher in vivo expression and superior antitumor efficacy. CAR-positive monocytes persisted in circulation for up to 48 hours post-intravenous injection, correlating with increased cytokine and chemokine levels in peripheral blood. In vitro studies showed selective expression of GPC3 CAR in up to 30% of monocytes, supporting the feasibility of this delivery platform.
Phase 1 Trial Details
The open-label, dose-escalation, Phase 1 trial is evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of MT-303 in adult patients with advanced or metastatic HCC with GPC3 overexpression. The trial is enrolling patients aged 18 and older with a histological diagnosis of advanced/recurrent or metastatic and/or unresectable HCC, measurable lesion per RECIST 1.1 criteria, an ECOG performance status grade of 0 or 1, a Child-Pugh score of class A, and adequate organ function.
MT-303 is administered via intravenous infusion until disease progression or unacceptable toxicity. Patients are enrolled in sequential dose-escalation cohorts to determine the dose-limiting toxicities of MT-303 and to establish the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D).
The primary endpoints of the trial include assessing the safety and tolerability profile, including the type, incidence, and severity of adverse events (AEs); RP2D; change from baseline in vital signs; change in laboratory parameters; and change from baseline in ECG parameters. Secondary endpoints include assessing pharmacokinetics and AEs of special interest.
The first patient with HCC was dosed with MT-303 in August 2024. "Myeloid has rapidly advanced MT-303 into first-in-human testing as our second in vivo CAR clinical program. Dose escalation of MT-303 and MT-302 continues, and we are encouraged by the ongoing biologic indications of proof-of-mechanism, as well as the early observed safety and efficacy experience," said Matthew Maurer, MD, chief medical officer of Myeloid.
