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    2ms
    Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. (PubMed, Gut)
    Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244).
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • GZMB (Granzyme B) • HDAC1 (Histone Deacetylase 1) • STAT1 (Signal Transducer And Activator Of Transcription 1) • GSDME (Gasdermin E)
    |
    Keytruda (pembrolizumab) • zabinostat (CXD101)
    over1year
    Epigenetic activation of tumoral INFγ response and pyroptosis overcomes immunotherapy resistance in hepatocellular carcinoma (IDDF 2023)
    Based on these findings, industrial support for the Phase II clinical study of CXD101 plus anti-PD-1 has been secured to provide new epigenetic immunotherapy for ICB-resistant patients. This project is supported by the CRF (C4045-18W), GRF (14115820), TRS (T11-706/18-N), Li Ka Shing Foundation, CUHK Strategic Seed Funding for Collaborative Research Scheme.
    PD(L)-1 Biomarker • IO biomarker
    |
    IFNG (Interferon, gamma) • STAT1 (Signal Transducer And Activator Of Transcription 1) • GSDME (Gasdermin E)
    |
    zabinostat (CXD101)
    over1year
    CXD101 in Immunotherapy-related Liver Cancer (clinicaltrials.gov)
    P2, N=44, Not yet recruiting, Stephen Chan Lam
    New P2 trial • Checkpoint inhibition
    |
    sorafenib • Lenvima (lenvatinib) • Aibining (geptanolimab) • zabinostat (CXD101)
    over2years
    A selective class I HDAC inhibitor recovers intratumoral interferon signaling to overcome immune-checkpoint blockade resistance in hepatocellular carcinoma (P923) (IMMUNOLOGY 2022)
    Moreover, we found a novel selective class I histone deacetylase (HDAC) inhibitor, CXD101, significantly recovered intratumoral IFNγ signaling pathway and synergised with PD-L1 antibody to eradicate tumor and prolong survival in our ICB resistant mouse models. We will further elucidate the epigenetic processes in regulating anti-tumor immunity and the detailed mechanism-of-action of CXD101 plus ICB therapy in our preclinical models, aiming to provide novel mechanism-based immunotherapeutic strategy for HCC patients.
    Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
    |
    IFNG (Interferon, gamma)
    |
    PD-L1 expression
    |
    zabinostat (CXD101)
    over3years
    PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov)
    P1/2, N=0, Withdrawn, University College, London | N=45 --> 0 | Trial completion date: Oct 2027 --> Apr 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Oct 2026 --> Apr 2024
    Enrollment change • Trial completion date • Trial withdrawal • Trial primary completion date • Combination therapy • Epigenetic controller
    |
    BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
    |
    BCL6 translocation
    |
    Keytruda (pembrolizumab) • zabinostat (CXD101)
    over3years
    Immune modulation underpins the anti-cancer activity of HDAC inhibitors. (PubMed, Mol Oncol)
    The altered TME reflected enhanced anti-tumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti-PD1 and anti-CTLA4. The ability of CXD101 to re-instate immune-relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
    |
    zabinostat (CXD101)
    almost4years
    PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov)
    P1/2, N=45, Not yet recruiting, University College, London | Trial completion date: Jan 2026 --> Oct 2027 | Trial primary completion date: Jan 2025 --> Oct 2026
    Trial completion date • Trial primary completion date • Combination therapy • Epigenetic controller
    |
    BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
    |
    BCL6 translocation
    |
    Keytruda (pembrolizumab) • zabinostat (CXD101)
    4years
    PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov)
    P1/2, N=45, Not yet recruiting, University College, London | Trial completion date: Apr 2025 --> Jan 2026 | Trial primary completion date: Apr 2024 --> Jan 2025
    Trial completion date • Trial primary completion date • Combination therapy • Epigenetic controller
    |
    BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
    |
    BCL6 translocation
    |
    Keytruda (pembrolizumab) • zabinostat (CXD101)