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Combined Immunotherapy and Particle Therapy for Advanced HCC with Macrovascular Invasion: Phase Ib DEPARTURE Trial

ABSTRACT: Hepatocellular carcinoma (HCC) with macrovascular invasion carries a poor prognosis, necessitating novel therapeutic strategies. This phase Ib trial evaluated the safety and preliminary efficacy of combining carbon-ion radiotherapy with immune checkpoint inhibitors in patients with advanced HCC. RNA-seq was conducted to investigate changes in the tumor microenvironment, aiming to identify molecular signatures predictive of response or resistance to the combination therapy. The reduction group showed enrichment of pathways related to inflammation, complement activation, which are often associated with immune activity. In contrast, the progression group exhibited enrichment of pathways linked to mesenchymal characteristics and angiogenesis, processes that may correlate with reduced therapy efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287319 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:IntroductionAdvanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.Methods and analysisThis phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B.Ethics and disseminationThis study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication.Trial registration numberjRCT2031210046.

Project description:Background: The objective response rate of anti-programmed death receptor 1 (PD-1) immunotherapy in hepatocellular carcinoma (HCC) remains limited. The tumor immunosuppressive microenvironment mediated by regulatory T cells (Tregs) is a key bottleneck. The traditional Chinese medicine (TCM) compound Fuzheng Jiedu Xiaoji Formula (FZJDXJ) has been proven to improve the clinical efficacy of adjuvant therapy for HCC and remodel the tumor immunosuppressive microenvironment, yet its sensitizing effect and underlying mechanism on PD-1 inhibitors remain unclear.Methods: A total of 55 clinical patients were enrolled, who received either immunotherapy alone or FZJDXJ combined with immunotherapy for 3 cycles. The 1-year efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and peripheral immune responses were analyzed by multicolor flow cytometry. A Hepa1-6 orthotopic HCC mouse model was established and divided into four groups: model group, anti-PD-1 monotherapy group, FZJDXJ monotherapy group, and FZJDXJ combined with anti-PD-1 group. Tumor growth, as well as the function of Tregs and CD8+T cells in the periphery and tumor infiltrates, were assessed. Transcriptomic and metabolomic analyses were conducted to explore the molecular mechanisms and metabolic characteristics of the tumor microenvironment, with in vitro for validation.Results: In the clinical cohort, the 1-year disease control rate (DCR) of the combination therapy group was significantly increased by 28.5% (83.3% vs. 54.8%, p = 0.026), and the incidence of adverse events was reduced by 36.3% (25% vs. 61.3%, p = 0.010) compared with the immunotherapy-alone group. Multicolor flow cytometry confirmed that the combination therapy significantly decreased the proportion of peripheral Tregs and increased the ratio of tissue-resident memory CD8+T cells (TRM) with effector function. In HCC-bearing mice, the combination therapy sensitized the anti-tumor effect of anti-PD-1 treatment, ameliorated immune-related hepatitis and nephritis induced by immunotherapy, enhanced the proportion, cytotoxicity, and proliferation of peripheral and tumor-infiltrating CD8+T cells, and markedly reduced the infiltration and proliferation of Tregs. Multi-omics analyses revealed that the combination therapy significantly downregulated the DHCR7-TFR1 signaling pathway, inhibiting lipotoxicity caused by excessive lipid accumulation in Tregs, which was identified as the central mechanism of the combination therapy for HCC. In vitro confirmed that FZJDXJ containing serum suppressed the activation of the DHCR7-TFR1 signaling pathway, inhibited excessive lipid accumulation in Tregs (detected by BODIPY493/503-FITC, Liperfluo, ROS, and MitoSOX), and attenuated the immunosuppressive capacity of Tregs and their secretion of TGF-βand IL-10 cytokines.Conclusion: FZJDXJ enhances the efficacy of anti-PD-1 therapy for HCC by inhibiting Treg cholesterol metabolic reprogramming and lipotoxicity, thereby relieving the excessive immunosuppression of CD8+T cells by Tregs. This study provides a novel mechanism and clinical evidence for the combination of TCM compounds with immunotherapy for HCC.

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Combined Immunotherapy and Particle Therapy for Advanced HCC with Macrovascular Invasion: Phase Ib DEPARTURE Trial

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