title: Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer.
abstract: Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Sukeshi
authors.initials: S
authors.lastname: Patel
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Goros
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Michalek
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Curiel
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001343:Autophagy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000627:therapeutic use*; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D006886:Hydroxychloroquine; D000077337:Vorinostat
keywords: autophagy; colorectal cancer; hydroxychloroquine; immunity; vorinostat