Directed evolution generates an oncolytic Sindbis virus with enhanced tumor-killing capacity in osteosarcoma

Area of Science:

• Oncolytic virotherapy
• Cancer biology
• Viral evolution

Background:

• Osteosarcoma frequently metastasizes, leading to poor patient survival rates.
• Current therapies struggle to effectively target metastatic osteosarcoma.
• Oncolytic viruses offer a promising strategy for cancer treatment by selectively destroying tumor cells and stimulating immune responses.

Purpose of the Study:

• To enhance the therapeutic efficacy of Sindbis virus (SINV) against osteosarcoma.
• To overcome the limited replication of wild-type SINV in osteosarcoma cells.

Main Methods:

• Directed evolution of SINV by serial passaging in osteosarcoma cell lines (HOS and U2OS).
• Identification of mutations conferring enhanced viral replication and cytotoxicity.
• Evaluation of the modified virus (SINV-P438L) in vitro and in vivo osteosarcoma models.

Main Results:

• A variant, SINV-P438L, with a mutation in nsP2, demonstrated increased replication and transcription efficiency in osteosarcoma cells.
• SINV-P438L exhibited enhanced infectivity and cytotoxicity, activating apoptosis-associated signals.
• SINV-P438L showed superior antitumor effects in osteosarcoma and other tumor models in vivo, with no observed toxicity in normal tissues.

Conclusions:

• SINV-P438L represents a promising oncolytic virus candidate for osteosarcoma treatment.
• The enhanced viral replication and antitumor activity support its potential clinical application.
• SINV-P438L may also be applicable to other cancer types.