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Growth, Purification, and Titration of Oncolytic Herpes Simplex Virus
Published on: May 13, 2021
Oncolytic virus therapy using genetically engineered herpes simplex viruses
1Department of Neurosurgery, The University of Tokyo, Tokyo, Japan. toudou-nsu@umin.ac.jp
Abstract:
Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for cancer. They can replicate in situ, spread, and exhibit oncolytic activity via a direct cytocidal effect. In addition, oncolytic HSV-1 can transfer and express foreign genes in host cells. The phase I clinical study with G207, a double-mutated HSV-1, in recurrent malignant glioma patients has shown that oncolytic HSV-1 can be safely administered into human brains. The therapeutic benefits of oncolytic HSV-1 depend on the extent of both intratumoral viral replication and induction of host antitumor immune responses. We develop new-generation oncolytic HSV-1 by enhancing these properties while retaining the safety features. G47delta was created from G207 by introducing another genetic mutation. Compared with G207, G47delta showed 1) better stimulation of human antitumor immune cells, 2) better growth properties leading to higher virus yields and increased cytopathic effect in vitro, 3) better antitumor efficacy in both immuno-competent and -incompetent animals, and 4) preserved safety in the brain of HSV-1-sensitive mice. Preparation is under way for a clinical trial using G47delta in progressive glioblastoma patients. G47delta is also suited as a backbone vector for expressing foreign molecules. Using bacterial artificial chromosome and two DNA recombinases, we have created an "armed" oncolytic HSV-1 generation system that allows insertion of transgene(s) into the genome of G47delta in a rapid and accurate manner. We found that expression of immunostimulatory molecules can significantly enhance the antitumor efficacy of G47delta. Based on these advances, we anticipate that oncolytic virus therapy using oncolytic HSV-1 will soon be established as an important modality of cancer treatment.
Insights
Genetically engineered herpes simplex virus type 1 (HSV-1) shows promise for cancer treatment. A new version, G47delta, demonstrates enhanced immune response and tumor-killing ability, paving the way for clinical trials.
Area of Science:
- Oncolytic virotherapy
- Cancer immunotherapy
- Viral gene therapy
Background:
- Genetically engineered herpes simplex virus type 1 (HSV-1) exhibits oncolytic activity and can deliver foreign genes.
- Previous studies with G207 demonstrated the safety of oncolytic HSV-1 in human brain tumors.
- Therapeutic success relies on viral replication and host antitumor immune responses.
Purpose of the Study:
- To develop a new-generation oncolytic HSV-1 with enhanced antitumor properties and retained safety.
- To evaluate the efficacy and safety of G47delta, a modified HSV-1, in preclinical models.
- To establish a system for creating "armed" oncolytic HSV-1 for enhanced immune stimulation.
Main Methods:
- Development of G47delta, a triple-mutated HSV-1 derived from G207.
- In vitro and in vivo evaluation of G47delta's replication, cytopathic effects, and antitumor efficacy.
- Creation of an "armed" HSV-1 system using bacterial artificial chromosome and DNA recombinases for transgene insertion.
- Assessment of G47delta's safety in the brain of HSV-1-sensitive mice.
Main Results:
- G47delta demonstrated superior stimulation of human antitumor immune cells compared to G207.
- G47delta exhibited enhanced growth properties, higher virus yields, and increased cytopathic effects in vitro.
- G47delta showed improved antitumor efficacy in both immunocompetent and immunodeficient animal models.
- G47delta maintained safety in the brain, and expression of immunostimulatory molecules significantly enhanced its antitumor efficacy.
Conclusions:
- G47delta represents an advanced oncolytic HSV-1 with enhanced efficacy and safety for cancer treatment.
- The development of an "armed" HSV-1 generation system allows for rapid and accurate transgene insertion.
- Oncolytic HSV-1 therapy, particularly with armed variants, holds significant potential as a future cancer treatment modality.
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