Primary liver cancer (Hepatocellular carcinoma, HCC) represents a major challenge in clinical oncology and poses a serious threat to public health. In recent years, the application of immune checkpoint inhibitors (ICIs) has transformed the landscape of cancer therapy, demonstrating remarkable efficacy in a subset of patients. However, due to the unique immune-tolerant microenvironment of the liver, tumor cells can evade host immune surveillance, leading to reduced immune cell infiltration and T cell exhaustion. Consequently, patients with advanced HCC often respond poorly to existing ICI therapies. Transforming growth factor-beta (TGF-β), a key regulator of T cell immune responses, is highly expressed in the tumor microenvironment and mediates immune evasion by inducing regulatory T cell (Treg) differentiation and suppressing the effector functions of CD8⁺ T cells. Therefore, simultaneous blockade of immune checkpoints and the TGF-β signaling pathway represents a promising strategy to reverse immune tolerance in liver tumors. Based on the above mechanisms, our research team has developed an RNA formulation (YMN-A02 bifunctional RNA formulation) encapsulated in TM10-LNP, which encodes a bifunctional fusion protein combining a CTLA-4 antibody and a TGF-β trap. Preclinical studies have shown that this formulation effectively activates antitumor immune responses and inhibits tumor growth in orthotopic liver cancer animal models. This study proposes a Phase I clinical trial to evaluate the safety, tolerability, immunogenicity, and preliminary efficacy of this formulation in patients with advanced primary liver cancer who have failed standard treatment, aiming to provide a new strategy for overcoming immune tolerance in liver tumors and improving the response rate to immunotherapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Enrolled subjects will receive a 100 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Enrolled subjects will receive a 250 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Enrolled subjects will receive a 500 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Enrolled subjects will receive a 1000 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
West China Hospital
Chengdu, Sichuan, China
Occurrence of Dose-Limiting Toxicity (DLT)
Observe and record the occurrence of DLTs. DLT is defined as treatment-related adverse events or clinically significant laboratory abnormalities occurring during the DLT observation period, graded according to NCI CTCAE v5.0.
Time frame: From first dose to 14 days after the third dose, approximately Day 0 to Day 42
Progression-Free Survival (PFS)
Assess disease progression per RECIST v1.1, calculating the time from start of treatment to first documented disease progression or death from any cause.
Time frame: Within 2 years after the first dose
Objective Response Rate (ORR)
Tumor response assessed per RECIST v1.1 for solid tumors. ORR is the proportion of patients whose tumor volume reduction reaches a predefined value and is maintained for a minimum required duration, calculated as the sum of complete response (CR) and partial response (PR) rates.
Time frame: Within 6 months after the first dose
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