Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses

Area of Science:

• Oncolytic virotherapy
• Cancer immunotherapy
• Tumor immunology

Background:

• Oncolytic virotherapy often leads to early tumor response and subsequent recurrence.
• Oncolytic viruses like VSV-IFN-β can induce mutations (e.g., in CSDE1) that promote tumor escape.
• Specific mutations, such as in the CSDE1 gene, are key drivers of tumor escape post-virotherapy.

Purpose of the Study:

• To investigate exploiting tumor escape mutations for enhanced oncolytic virotherapy.
• To demonstrate the efficacy of sequential oncolytic virus delivery against escaping tumors.
• To explore combining virotherapy with immune checkpoint blockade for improved anti-tumor immunity.

Main Methods:

• Sequential *in vivo* administration of two distinct oncolytic VSVs.
• Analysis of tumor cell mutations, including a specific CSDE1 point mutation.
• Evaluation of anti-tumor T-cell responses and combination therapy with CD200AR-L peptide.

Main Results:

• Sequential VSV delivery successfully cured tumors that would otherwise escape VSV-IFN-β therapy.
• The strategy effectively targeted tumor cells harboring the escape-promoting CSDE1 mutation.
• The treatment primed potent anti-tumor T-cell responses, synergizing with immune checkpoint blockade.

Conclusions:

• Exploiting viral escape mechanisms via sequential virotherapy offers a potent anti-cancer strategy.
• This approach can overcome tumor resistance to standard oncolytic virotherapy.
• Developing targeted viro-immunotherapies holds promise for treating recurrent and therapy-resistant cancers.