Abstract PO023: Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225

In addition to their canonical role in transcriptional regulation, Histone deacetylases (HDACs) regulate other cellular functions by maintaining a balance of lysine acetylation on key cellular proteins. HDAC inhibitors are under development for use in treating cancers, neurological, and immunological diseases. A barrier to the development of HDAC inhibitors has been the toxicity associated with non-selective pan-HDAC inhibitors, which simultaneously inhibit multiple HDAC isoforms. Isoform selective HDAC inhibitors offer disease targeting with an improved toxicity profile. HDAC6 presents an important target due to its role in immune regulatory processes involved in antitumor immune responses. We have shown that selective inhibition of HDAC6 regulates macrophages to recognize, phagocyte, and present antigens to the adaptive immune system. Treatment with our selective HDAC6 inhibitor, SP-2-225, was shown to enhance the production of cancer-associated antigens and macrophage antigen cross-presentation to T cells. Through a non-cytotoxic mechanism, SP-2-225 significantly reduced the tumor volume in a syngeneic SM1 melanoma model. Analysis of the tumors from treated animals showed a significant shift in the M1/M2 ratio of the infiltrating macrophages as compared to control, indicating that SP-2-225 caused a pro-inflammatory, antitumor shift in the macrophage equilibrium surrounding the tumor. This was identified as the putative mechanism through adoptive cell therapy where macrophages from naive animals were harvested and treated ex-vivo with SP-2-225. Reimplantation of these SP-2-225 ex-vivo treated macrophages resulted in reduced tumor volumes when compared to both vehicle and untreated macrophage animal cohorts. We propose that this selective inhibitor of HDAC6 offers potential as a stand-alone cancer therapy and in combination with other immunotherapies and radiation treatments. Citation Format: Scott Grindrod, Satish Noonepalle, Nima Aghdam, Alfredo Velena, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Mira Jung, Anatoly Dritschilo, Alejandro Villagra. Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225 [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO023.