Imofinostat, a histone deacetylase inhibitor, enhances anti-tumoral activity on colorectal cancer with an immune checkpoint inhibitor

Background: Histone deacetylase (HDAC) inhibitors have been shown to exert immunomodulatory effects and enhance immune responses elicited by immune checkpoint inhibitors (ICIs). Imofinostat (ABT-301) is an HDAC inhibitor with potent activity against class I HDACs and moderate activity against class IIb HDACs. In this study, we investigated the therapeutic efficacy and underlying immunomodulatory mechanisms of imofinostat combined with ICI-based regimens in colorectal cancer (CRC). Methods: Imofinostat was evaluated in combination with ICIs (anti-mPD-1 or anti-PD-L1) in both murine syngeneic (CT26) and human microsatellite stable (MSS) CRC cell line-derived xenograft (CDX) models (HT29) with or without antiangiogenic agent aflibercept. Transcriptomic profiling was performed using the NanoString IO360 panel, while immune cell alterations and functional markers were analyzed by flow cytometry and immunohistochemistry (IHC). Results: In the CT26 syngeneic mouse model, the combination of imofinostat with avelumab (anti-PD-L1) induced complete tumor regression in 7 of 8 animals. Notably, of those achieving complete remission, 6 of 7 remained tumor-free following tumor re-challenge, indicating the establishment of durable anti-tumor immunity. This combination demonstrated superior efficacy compared to the pan-HDAC inhibitor vorinostat and the class I-selective HDAC inhibitor tucidinostat in parallel CT26 models. In the HT29 CRC model co-engrafted with patient-derived PBMCs, an additive anti-tumor effect was observed with the combination of imofinostat and nivolumab (anti-PD-1), which was further enhanced by the addition of aflibercept. Gene Set Enrichment Analysis (GSEA) revealed that imofinostat, alone and in combination, significantly enriched gene signatures associated with central memory T-cells. The combination treatment also increased infiltrated cytotoxic CD4⁺ and CD8⁺ T cells (IFN-gamma⁺ or GzmB⁺) and reduced monocytic-myeloid-derived suppressor cells (M-MDSCs) in PBMCs. Conclusion: Imofinostat synergizes with ICI by targeting mechanisms of immune suppression, including the reduction of M-MDSCs in PBMCs, while concurrently promoting the development of robust cytotoxic and memory T-cell responses. This provides a strong rationale for the clinical investigation of imofinostat in combination with ICIs for CRC.