Innovative mRNA CAR Therapy MT-303 Under Study for Liver Cancer
MT-303, a novel GPC3-targeting mRNA/lipid nanoparticle chimeric antigen receptor therapy, enhances cytokine-driven immune response and tumor cytotoxicity.
Microscopic, photorealistic image of liver tumor cells - Generated with Adobe Firefly
MT-303, a novel GPC3-targeting chimeric antigen receptor (CAR) mRNA/lipid nanoparticle formulation, represents a promising therapeutic option in hepatocellular carcinoma (HCC).1
This agent allows myeloid cells to directly kill tumor cells and support the establishment of a cytokine-mediated immune response.1 It is currently undergoing evaluation in a phase 1 trial (NCT06478693) for the treatment of patients with HCC.
MT-303 is made of a GPC3-specific single-chain variable fragment and a short flexible linker fused with a truncated human CD89.1 Preclinical research to investigational new drug-enabling studies, have focused on characterizing the expression and function of the GPC3 CAR in vitro.
"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, in a press release. "The clinical observations extend the earlier preclinical results, that also demonstrated selective activation of CAR myeloid cells and robust anti-tumor activity in mouse hepatocellular tumor models."
Initially, this mRNA construct exhibited limited CAR expression duration, which led to modifications to its 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.1
In a HepG2 HCC xenograft model, the optimized mRNA construct resulted in higher in vivo expression and superior antitumor efficacy. CAR-positive monocytes continued in circulation for up to 48 hours post-intravenous injection and were linked to increased cytokine and chemokine levels in peripheral blood.1
Additional in vitro studies showed selective expression of GPC3 CAR in up to 30% of monocytes, further supporting the feasibility of this delivery platform.
Behind the Phase 1 Study of MT-303
In the open-label, dose-escalation, phase 1 trial of MT-303, experts are assessing the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the agent when given as a treatment for adult patients with advanced or metastatic HCC with overexpressed GPC3.2
The study is enrolling patients aged 1 and older with a histological diagnosis of advanced/recurrent or metastatic and/or unresectable HCC.2 Enrollment is open to those with a measurable lesion per RECIST 1.1 criteria, an ECOG performance status grade of 0 or 1, a Child-Pugh score that is class A, and adequate organ function.
MT-303 is being administered to patients via intravenous infusion until lack of tolerability or progression. Patients are being enrolled in sequential dose-escalation cohorts. Investigators aim to determine the dose-limiting toxicities of MT-303 and plan to establish the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the agent.
Primary end points of the trial are to determine 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 end points include assessing pharmacokinetics and AEs of special interest.
The first patient with HCC was dosed with MT-303 in the study in August 2024.3
REFERENCES
Myeloid Therapeutics announces SITC 2024 oral presentation on MT-303, the first in vivo GPC3 targeting mRNA CAR in human studies for advanced hepatocellular carcinoma (HCC). News release. Myeloid Therapeutics, Inc. November 8, 2024. Accessed December 13, 2024. https://tinyurl.com/3m2enrts
A study of MT-303 in adults with advanced or metastatic GPC3-expressing cancers, including HCC. ClinicalTrials.gov. Updated July 1, 2024. Accessed December 13, 2024. https://clinicaltrials.gov/study/NCT06478693
Myeloid Therapeutics initiatespatient dosing with MT-303, a novel GPC3 targeting RNA CAR, in phase 1 study for advanced hepatocellular carcinoma (HCC). News release. Myeloid Therapeutics, Inc. July 31, 2024. Accessed December 13, 2024. https://tinyurl.com/3vux2psc
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