A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus.
Replication-selective oncolytic herpes simplex virus (HSV) has shown considerable promise as an antitumor agent. Although the current oncolytic HSVs were exclusively constructed from HSV-1, HSV-2 has several unique features that could be exploited to convert the virus to an oncolytic agent. The N-terminus of the HSV-2 ICP10 gene product contains a well-defined serine/threonine protein kinase (PK) domain, which can activate the Ras/MEK/MAPK mitogenic pathway and thus facilitate efficient HSV-2 replication. Because the Ras signaling pathway is a key regulator of normal cell growth and malignant transformation, it is aberrantly activated in many human tumors. Here we report that a mutant HSV-2 (FusOn-H2), constructed by replacing the PK domain of ICP10 with the gene encoding the green fluorescent protein, can selectively replicate in and thus lyse tumor cells. Moreover, infection of FusOn-H2 led to syncytia formation in tumor cells, providing an additional tumor-destroying mechanism. A single moderate-dose injection of FusOn-H2 into established breast cancer xenografts completely eradicated the tumors in more than 80% of the animals, leading to their long-term survival. We conclude that this HSV-2 mutant is a safe and potent oncolytic agent useful for the treatment of malignant solid tumors such as breast cancer.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Xinping
X
Fu
Lihua
L
Tao
Rong
R
Cai
Jonathan
J
Prigge
Xiaoliu
X
Zhang
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000821:virology; D018258:Herpesvirus 2, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D050504:Oncolytic Viruses / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012264:Ribonucleotide Reductases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D016019:Survival Analysis; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D049452:Green Fluorescent Proteins; C100671:ICP10 protein, herpes simplex virus type 2; D012264:Ribonucleotide Reductases; D017346:Protein Serine-Threonine Kinases