title: Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer.
abstract: Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately 73-fold higher concentration of AdVince is needed to induce a similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Justyna
authors.initials: J
authors.lastname: Leja-Jarblad
authors.forename: Angelica
authors.initials: A
authors.lastname: Loskog
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.forename: Valeria
authors.initials: V
authors.lastname: Giandomenico
authors.forename: Kjell
authors.initials: K
authors.lastname: Oberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
mesh_terms: D018278:Carcinoma, Neuroendocrine / Q000097:blood / Q000473:pathology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000556:secondary* / Q000628:therapy*; D018358:Neuroendocrine Tumors / Q000097:blood / Q000473:pathology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology; D011951:Receptors, Complement / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D011951:Receptors, Complement; D049452:Green Fluorescent Proteins
keywords: AdVince; Immunotherapy; Liver metastases; Neuroendocrine cancer; Oncolytic adenovirus