Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies.

Affiliation

Ishino R(1), Kawase Y(2), Kitawaki T(2), Sugimoto N(3), Oku M(4), Uchida S(4), Imataki O(4), Matsuoka A(5), Taoka T(5), Kawakami K(6), van Kuppevelt TH(7), Todo T(8), Takaori-Kondo A(2), Kadowaki N(9).
Author information:
(1)Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
(2)Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
(3)Department of Clinical Application, Center for iPS Cell Research and Application
(CiRA), Kyoto University, Kyoto, Japan.
(4)Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
(5)Division of Internal Medicine, Sakaide City Hospital, Sakaide, Japan.
(6)Division of Hematology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
(7)Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
(8)Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
(9)Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan. Electronic address: [Email]

Abstract

Oncolytic herpes simplex virus type 1 (HSV-1) has been investigated to expand its application to various malignancies. Because hematopoietic cells are resistant to HSV-1, its application to hematological malignancies has been rare. Here, we show that the third generation oncolytic HSV-1, T-01, infected and killed 18 of 26 human cell lines and 8 of 15 primary cells derived from various lineages of hematological malignancies. T-01 replicated at low levels in the cell lines. Viral entry and the oncolytic effect were positively correlated with the expression level of nectin-1 and to a lesser extent 3-O-sulfated heparan sulfate, receptors for glycoprotein D of HSV-1, on tumor cells. Transfection of nectin-1 into nectin-1-negative tumor cells made them susceptible to T-01. The oncolytic effects did not appear to correlate with the expression or phosphorylation of antiviral molecules in the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) and PKR-eIF2α pathways. In an immunocompetent mouse model, intratumoral injection of T-01 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infiltration of antigen-specific CD8+ T cells. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Nectin-1 expression may be the most useful biomarker for optimal efficacy.