2. Academic Validation
  3. Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling T-cells, myeloid derived suppressor and NK cells

Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling T-cells, myeloid derived suppressor and NK cells

  • J Exp Clin Cancer Res. 2023 Mar 18;42(1):67. doi: 10.1186/s13046-023-02628-x.
Adriana Amaro # 1,  Francesco Reggiani # 1,  Daniela Fenoglio # 1 2,  Rosaria Gangemi 1,  Anna Tosi 3,  Alessia Parodi 1,  Barbara Banelli 1,  Valentina Rigo 1,  Luca Mastracci 1,  Federica Grillo 1,  Alessandra Cereghetti 4,  Aizhan Tastanova 4,  Adhideb Ghosh 5,  Fabio Sallustio 6,  Laura Emionite 1,  Antonio Daga 1,  Tiziana Altosole 1,  Gilberto Filaci 1 2,  Antonio Rosato 3 7,  Mitchell Levesque 4,  Michele Maio 8,  Ulrich Pfeffer 9,  Michela Croce 1,  EPigenetic Immune-oncology Consortium Airc (EPICA) consortium
Affiliations

Affiliations

  • 1 IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy.
  • 2 Department of Internal Medicine, University of Genova, Genova, Italy.
  • 3 Immunology and Molecular Oncology Diagnostics, Istituto Oncologico Veneto IRCCS, Padova, Italy.
  • 4 Department of Dermatology, University of Zurich, University Hospital of Zurich, Zurich, Switzerland.
  • 5 Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
  • 6 Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy.
  • 7 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
  • 8 University of Siena, Siena, Italy.
  • 9 IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy. ulrich.pfeffer@hsanmartino.it.
  • # Contributed equally.
PMID: 36934257 DOI: 10.1186/s13046-023-02628-x
Abstract

Background: The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blockade has dramatically improved the overall survival rate for malignant melanoma. Immune checkpoint blockers (ICBs) limit the tumor's immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICBs are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437).

Methods: We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking Antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor's and the host's responses under different treatments by flow cytometry, multiplex immunofluorescence and methylation analysis.

Results: In combination with ICBs, Guadecitabine significantly reduced subcutaneous tumor growth as well as metastases formation compared to ICBs and Guadecitabine treatment. In particular, Guadecitabine greatly enhanced the efficacy of combined ICBs by increasing effector memory CD8+ T cells, inducing effector NK cells in the spleen and reducing tumor infiltrating regulatory T cells and myeloid derived suppressor cells (MDSC), in the tumor microenvironment (TME). Guadecitabine in association with ICBs increased serum levels of IFN-γ and IFN-γ-induced chemokines with anti-angiogenic activity. Guadecitabine led to a general DNA-demethylation, in particular of sites of intermediate methylation levels.

Conclusions: These results indicate Guadecitabine as a promising epigenetic drug to be added to ICBs therapy.

Keywords

Anti-CTLA-4; Anti-PD-1; Guadecitabine; MDSC; Melanoma; Treg; Tumor microenvironment.

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