"The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor mi" by Damian Kovalovsky, Satish Noonepalle et al.
 

The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy

Damian Kovalovsky, Avstera Therapeutics Corp, 365 Phoenixville Pike, Malvern, PA 19355, USA.
Satish Noonepalle, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.
Manasa Suresh, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.
Dileep Kumar, Avstera Therapeutics Corp, 365 Phoenixville Pike, Malvern, PA 19355, USA.
Michael Berrigan, McCormick Genomics and Proteomics Center, School of Medicine and Health Sciences, The George Washington University, 2300 Eye Street NW, Ross Hall 541, Washington, DC 20037, USA.
Nithya Gajendran, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.
Sumit Upadhyay, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.
Anelia Horvath, McCormick Genomics and Proteomics Center, School of Medicine and Health Sciences, The George Washington University, 2300 Eye Street NW, Ross Hall 541, Washington, DC 20037, USA.
Allen Kim, McCormick Genomics and Proteomics Center, School of Medicine and Health Sciences, The George Washington University, 2300 Eye Street NW, Ross Hall 541, Washington, DC 20037, USA.
David Quiceno-Torres, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.
Karthik Musunuri, Avstera Therapeutics Corp, 365 Phoenixville Pike, Malvern, PA 19355, USA.
Alejandro Villagra, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, E416 Research Bldg., Washington, DC 20057, USA.

Document Type

Journal Article

Publication Date

11-15-2024

Journal

Science advances

Volume

10

Issue

46

DOI

10.1126/sciadv.adp3687

Abstract

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

Department

Biochemistry and Molecular Medicine

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