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.
Fu
Xinping
X
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Tao
Lihua
L
Cai
Rong
R
Prigge
Jonathan
J
Zhang
Xiaoliu
X
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