Targeting epigenetic regulation and post-translational modification with 5-Aza-2’ deoxycytidine and SUMO E1 inhibition augments T-cell receptor therapy

• Published in: Journal for immunotherapy of cancer 2024-09, Vol.12 (9), p.e008654
• Main Authors: Kroonen, Jessie S, Wouters, Anne K, de Graaf, Ilona J, Remst, Dennis F G, Kumar, Sumit, Wachsmann, Tassilo L A, Teunisse, Amina F A S, Roelands, Jessica P, de Miranda, Noel F C C, Griffioen, Marieke, Heemskerk, Mirjam H M, Vertegaal, Alfred C O
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Cell Line, Tumor; Cells; Combination therapy; Cytotoxicity; Decitabine - pharmacology; Decitabine - therapeutic use; DNA methylation; Drug dosages; Epigenesis, Genetic - drug effects; Epigenetics; Humans; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Interferon; Leukemia; Lymphocytes; Medical prognosis; Mice; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - metabolism; Original Research; Protein Processing, Post-Translational; Receptors, Antigen, T-Cell - metabolism; T cell; T cell Receptor - TCR; Toxicity
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008654

BackgroundCellular immunotherapy using modified T cells offers new avenues for cancer treatment. T-cell receptor (TCR) engineering of CD8 T cells enables these cells to recognize tumor-associated antigens and tumor-specific neoantigens. Improving TCR T-cell therapy through increased potency and in vivo persistence will be critical for clinical success.MethodsWe evaluated a novel drug combination to enhance TCR therapy in mouse models for acute myeloid leukemia (AML) and multiple myeloma (MM).ResultsCombining TCR therapy with the SUMO E1 inhibitor TAK981 and the DNA methylation inhibitor 5-Aza-2’ deoxycytidine resulted in strong antitumor activity in a persistent manner against two in vivo tumor models of established AML and MM. We uncovered that the drug combination caused strong T-cell proliferation, increased cytokine signaling in T cells, improved persistence of T cells, and reduced differentiation towards exhausted phenotype. Simultaneously the drug combination enhanced immunogenicity of the tumor by increasing HLA and co-stimulation and surprisingly reducing inhibitory ligand expression.ConclusionCombining T-cell therapy with TAK981 and 5-Aza-2’ deoxycytidine may be an important step towards improved clinical outcome.