CREATE Medicines Initiates First-in-Class Frontline HCC Trial Combining In Vivo CAR Therapy MT-303 with Standard Immunotherapy
核心洞察
CREATE Medicines (搜索) has dosed the first patient in a frontline hepatocellular carcinoma (搜索) trial evaluating MT-303, an investigational in vivo GPC3 (搜索)-targeted CAR therapy, combined with standard-of-care atezolizumab and bevacizumab.
The study represents the first evaluation of MT-303 in treatment-naïve patients, where immune fitness is better preserved and there is greater potential for deep, durable responses to immunotherapy.
Clinical data from over 40 patients across CREATE's monotherapy programs have demonstrated in vivo CAR expression, immune activation, and tumor infiltration, providing biological rationale for combination therapy.
CREATE Medicines (搜索) has achieved a significant milestone in hepatocellular carcinoma (搜索) (HCC) treatment by dosing the first patient in a frontline clinical trial evaluating MT-303, an investigational in vivo GPC3 (搜索)-targeted CAR therapy, in combination with atezolizumab and bevacizumab. This marks the first time MT-303 is being evaluated in systemic treatment-naïve patients, where immune fitness is better preserved and there is greater potential for deep, durable responses to immunotherapy.
The multi-center, open-label, dose-escalation and expansion trial (NCT06478693) is designed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of MT-303 combined with the current global standard-of-care regimen for frontline HCC. The study will evaluate MT-303 in adults with unresectable or metastatic HCC who have not received prior systemic therapy.
Clinical Foundation and Mechanism of Action
Clinical correlative data from CREATE's ongoing monotherapy programs, including MT-302 and MT-303, have demonstrated in vivo CAR expression, immune activation, and tumor infiltration across more than 40 treated patients. These findings provide strong biological rationale for combination therapy and support the potential for additive or synergistic benefit when MT-303 is paired with atezolizumab and bevacizumab in the frontline setting.
MT-303 is an experimental, in vivo GPC3 (搜索)-targeted CAR therapy that selectively programs myeloid cells using CREATE's redosable mRNA-LNP system. The therapy is designed to produce CAR expression in circulating and tumor-infiltrating myeloid cells, direct cytotoxicity against GPC3-positive tumor cells, immune-modulating effects that recruit adaptive immunity, and repeat-dose capability with improved durability, requiring no lymphodepletion or ex vivo manufacturing.
GPC3 (搜索) is highly expressed across a majority of HCC cases and absent in normal adult tissue, making it an ideal target for directed immunotherapy. In the monotherapy dose escalation cohort of the MT-303 Phase 1/2 trial, the therapy demonstrated human proof-of-mechanism for in vivo CAR expression, myeloid-cell activation, tumor infiltration, evidence of clinical activity and the feasibility of repeat-dose regimens.
Safety Profile and Platform Advantages
MT-303 has shown a manageable and differentiated safety profile as a monotherapy, reinforcing the suitability of CREATE's mRNA-LNP in vivo CAR approach for use alongside established immunotherapies. The platform's flexibility, redosability, and absence of lymphodepletion requirements position MT-303 well for combination regimens in earlier-line settings where coordinated immune activation is essential.
"Advancing MT-303 into a frontline combination study represents an important evolution for the in vivo CAR field," said Matthew Maurer, M.D., Chief Medical Officer of CREATE Medicines (搜索). "Our monotherapy experience across MT-302 and MT-303 has generated compelling correlative evidence of immune activation, myeloid engagement, and tumor infiltration. These data, combined with MT-303's favorable safety and tolerability profile, support our confidence in evaluating the therapy alongside atezolizumab and bevacizumab. We believe MT-303 is well-positioned to drive deeper and more durable responses for patients with HCC."
Study Design and Objectives
The trial will characterize markers of immune activation, including CAR expression kinetics, cytokine/chemokine profiles, tumor infiltration by innate and adaptive immune cells, and early signs of antitumor activity. Data generated from this trial will inform recommended Phase 2 dose selection, further combination strategies, and potential expansion into additional earlier-line or biomarker-defined patient populations.
"New modalities capable of expanding the benefit of the current treatment options for hepatocellular carcinoma (搜索) are urgently needed," said Vladimir Andelkovic, M.D., FRACP, Principal Investigator, ICON Cancer Centre (搜索), Brisbane, Australia. "Adding the immune engagement potential of MT-303 to atezolizumab and bevacizumab in frontline systemic therapy, where immune fitness is more preserved, is both scientifically compelling and potentially clinically meaningful."
Clinical Context and Unmet Need
Liver cancer (搜索) is among the fastest-growing causes of cancer-related mortality globally, with more than 850,000 new cases diagnosed each year. Hepatocellular carcinoma (搜索) accounts for most liver cancer cases and often arises in the context of chronic liver disease, viral hepatitis, metabolic syndrome, or cirrhosis. Although recent advances in targeted agents and immunotherapies have improved patient outcomes, durable, long-term benefit remains limited for most patients. Once frontline therapies fail, treatment options become scarce, and prognosis worsens sharply.
CREATE Medicines (搜索) is a clinical-stage biotechnology company pioneering in vivo multi-immune programming. Its proprietary mRNA-LNP platform directly programs immune cells inside the body to deliver scalable, repeat-dose, off-the-shelf immunotherapies. With proven human validation and next-generation RNA technology, CREATE is advancing a pipeline of in vivo CAR therapies to transform outcomes in cancer, autoimmunity, and fibrosis.